Bromodomain Inhibitors

ABSTRACT

wherein Rx, Ry, Rx1, L1, G1, A1, A2, A3, and A4 have any of the values defined in the specification, and pharmaceutically acceptable salts thereof, that are useful as agents in the treatment of diseases and conditions, including inflammatory diseases, cancer, and AIDS. Also provided are pharmaceutical compositions comprised of one or more compounds of formula (I).

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation of U.S. application Ser. No.14/392,200, filed May 13, 2014, which is a National Stage entry ofinternational PCT/CN2014/077395, filed on May 13, 2014, which claims thebenefit of provisional application No. 61/840,559, filed on Jun. 28,2013. Each of the foregoing references are incorporated by reference intheir entireties.

BACKGROUND

Bromodomains refer to conserved protein structural folds which bind toN-acetylated lysine residues that are found in some proteins. The BETfamily of bromodomain containing proteins is comprised of four members(BRD2, BRD3, BRD4 and BRDt). Each member of the BET family employs twobromodomains to recognize N-acetylated lysine residues found primarily,but not exclusively, on the amino-terminal tails of histone proteins.These interactions modulate gene expression by recruiting transcriptionfactors to specific genome locations within chromatin. For example,histone-bound BRD4 recruits the transcription factor P-TEFb topromoters, resulting in the expression of a subset of genes involved incell cycle progression (Yang et al., Mol. Cell. Biol. 28: 967-976(2008)). BRD2 and BRD3 also function as transcriptional regulators ofgrowth promoting genes (LeRoy et al., Mol. Cell 30: 51-60 (2008)). BETfamily members were recently established as being important for themaintenance of several cancer types (Zuber et al., Nature 478: 524-528(2011); Mertz et al; Proc. Nat'l. Acad. Sci. 108: 16669-16674 (2011);Delmore et al., Cell 146: 1-14, (2011); Dawson et al., Nature 478:529-533 (2011)). BET family members have also been implicated inmediating acute inflammatory responses through the canonical NF-KBpathway (Huang et al., Mol. Cell. Biol. 29: 1375-1387 (2009)) resultingin the upregulation of genes associated with the production of cytokines(Nicodeme et al., Nature 468: 1119-1123, (2010)). Suppression ofcytokine induction by BET bromodomain inhibitors has been shown to be aneffective approach to treat inflammation-mediated kidney disease in ananimal model (Zhang, et al., J. Biol. Chem. 287: 28840-28851 (2012)).BRD2 function has been linked to predisposition for dyslipidemia orimproper regulation of adipogenesis, elevated inflammatory profiles andincreased susceptibility to autoimmune diseases (Denis, DiscoveryMedicine 10: 489-499 (2010)). The human immunodeficiency virus utilizesBRD4 to initiate transcription of viral RNA from stably integrated viralDNA (Jang et al., Mol. Cell, 19: 523-534 (2005)). BET bromodomaininhibitors have also been shown to reactivate HIV transcription inmodels of latent T cell infection and latent monocyte infection(Banerjee, et al, J. Leukocyte Biol. doi:10.1189/jlb.0312165). BRDt hasan important role in spermatogenesis that is blocked by BET bromodomaininhibitors (Matzuk, et al., Cell 150: 673-684 (2012)). Thus, compoundsthat inhibit the binding of BET family bromodomains to their cognateacetylated lysine proteins are being pursued for the treatment ofcancer, inflammatory diseases, kidney diseases, diseases involvingmetabolism or fat accumulation, and some viral infections, as well asfor providing a method for male contraception. Accordingly, there is anongoing medical need to develop new drugs to treat these indications.

SUMMARY

In one aspect the present invention provides for compounds of formula(I) or pharmaceutically acceptable salt thereof,

wherein

-   -   R^(x) is hydrogen or C₁-C₃ alkyl;    -   R^(y) is hydrogen or C₁-C₃ alkyl;    -   A¹ is N or CR¹, A² is N or CR², A³ is N or CR³; and A⁴ is N or        CR⁴; wherein zero, one, two, or three of A¹, A², A³, and A⁴ are        N;    -   R¹ is hydrogen, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl,        halogen, C₁-C₆ haloalkyl, CN, or NO₂;    -   R² is hydrogen, —S(O)₂R^(2a), —S(O)₂NR^(2b)R^(2c),        —N(R^(2b))S(O)₂R^(2a), or —(C₁-C₆ alkylenyl)-S(O)₂R^(2a);        wherein R^(2a) is C₁-C₆ alkyl or C₁-C₆ haloalkyl; and R^(2b) and        R^(2c) are each independently hydrogen, C₁-C₆ alkyl, or C₁-C₆        haloalkyl;    -   L¹ is O, N(H), or OCH₂ wherein the CH₂ moiety of OCH₂ is        attached to G¹;    -   R^(x1), G¹, R³, and R⁴, are selected from (i), (ii), (iii), or        (iv);    -   (i) R^(x1) is —CN, -G^(x1)-G^(x2), —(C₁-C₆        alkylenyl)-G^(x1)-G^(x2), —C(O)N(R^(xa))(R^(xb)), C₁-C₆ alkyl        substituted with one substituent selected from the group        consisting of —CN, —OR^(xb), —SR^(xb), —S(O)R^(xb),        —S(O)₂R^(xb), —NR^(xa)R^(xb), —C(O)R^(xb), —C(O)OR^(xb),        —C(O)NR^(xa)R^(xb), and —S(O)₂NR^(xa)R^(xb); C₂-C₆ alkenyl, or        C₂-C₆ alkynyl; wherein the C₂-C₆ alkenyl and C₂-C₆ alkynyl are        each independently substituted with one substituent selected        from the group consisting of —CN, —OR^(xc), —SR^(xc),        —S(O)R^(xc), —S(O)₂R^(xc), —NR^(xa)R^(xc), —C(O)R^(xc),        —C(O)OR^(xc), —C(O)NR^(xa)R^(xc), —S(O)₂NR^(xa)R^(xc), and        G^(x1);        -   G¹ is phenyl, C₃-C₆ cycloalkyl, C₅-C₆ heteroaryl, or C₄-C₆            heterocycle; wherein each G¹ is independently unsubstituted            or substituted with 1, 2, 3, 4, or 5 substituents            independently selected from the group consisting of R^(u)            and R^(v) groups;        -   R³ is R^(1a), —C(O)OH, —C(O)NR^(3a)R^(3b), —NR^(3a)R^(3b),            G^(3a), -G^(3a)-G^(3b), —(C₁-C₆ alkylenyl)-OR^(3a), —(C₁-C₆            alkylenyl)-NR^(3a)R^(3b), —(C₁-C₆ alkylenyl)-G^(3a), or            —(C₁-C₆ alkylenyl)-G^(3a)-G^(3b); and        -   R⁴ is R^(1a) or G⁴;    -   (ii) R^(x1) is —CN, -G^(x1)-G^(x2), —(C₁-C₆        alkylenyl)-G^(x1)-G^(x2), —C(O)N(R^(xa))(R^(xb)), hydrogen,        C₂-C₆ alkenyl, C₂-C₆ alkynyl, —C(O)OR^(ax1),        —C(O)NR^(bx1)R^(cx1), —C(O)R^(dx1), —S(O)₂R^(dx1),        —S(O)₂NR^(bx1)R^(cx1), G^(x1), C₁-C₆ haloalkyl, or C₁-C₆ alkyl;        wherein the C₁-C₆ alkyl, C₂-C₆ alkenyl, and C₂-C₆ alkynyl are        each optionally substituted with one substituent selected from        the group consisting of —CN, —OR^(xc), —SR^(xc), —S(O)R^(xc),        —S(O)₂R^(xc), —NR^(xa)R^(xc), —C(O)R^(xc), —C(O)OR^(xc),        —C(O)NR^(xa)R^(xc), —S(O)₂NR^(xa)R^(xc), and G^(x1);        -   G¹ is phenyl, C₃-C₆ cycloalkyl, C₅-C₆ heteroaryl, or C₄-C₆            heterocycle; wherein each G¹ is substituted with one R^(u)            group and is optionally further substituted with 1, 2, 3, 4,            or 5 R^(v) groups;        -   R³ is R^(1a), —C(O)OH, —C(O)NR^(3a)R^(3b), —NR^(3a)R^(3b),            -G^(3a), -G^(3a)-G^(3b), —(C₁-C₆ alkylenyl)-OR^(3a), —(C₁-C₆            alkylenyl)-NR^(3a)R^(3b), —(C₁-C₆ alkylenyl)-G^(3a), or            —(C₁-C₆ alkylenyl)-G^(3a)-G^(3b); and        -   R⁴ is R^(1a) or G⁴;    -   (iii) R^(x1) is —CN, -G^(x1)-G^(x2), —(C₁-C₆        alkylenyl)-G^(x1)-G^(x2), —C(O)N(R^(xa))(R^(xb)), hydrogen,        C₂-C₆ alkenyl, C₂-C₆ alkynyl, —C(O)OR^(ax1),        —C(O)NR^(bx1)R^(cx1), —C(O)R^(dx1), —S(O)₂R^(dx1),        —S(O)₂NR^(bx1)R^(cx1), G^(x1), C₁-C₆ haloalkyl, or C₁-C₆ alkyl;        wherein the C₁-C₆ alkyl, C₂-C₆ alkenyl, and C₂-C₆ alkynyl are        each optionally substituted with one substituent selected from        the group consisting of —CN, —OR^(xc), —SR^(xc), —S(O)R^(xc),        —S(O)₂R^(xc), —NR^(xa)R^(xc), —C(O)R^(xc), —C(O)OR^(xc),        —C(O)NR^(xa)R^(xc), —S(O)₂NR^(xa)R^(xc), and G^(x1);        -   G¹ is phenyl, C₃-C₆ cycloalkyl, C₅-C₆ heteroaryl, or C₄-C₆            heterocycle; wherein each G¹ is independently unsubstituted            or substituted with 1, 2, 3, 4, or 5 substituents            independently selected from the group consisting of R^(u)            and R^(v) groups;        -   R³ is —C(O)OH, —C(O)NR^(3a)R^(3b), —NR^(3a)R^(3b), G^(3a),            -G^(3a)-G^(3b), —(C₁-C₆ alkylenyl)-OR^(3a), —(C₁-C₆            alkylenyl)-NR^(3a)R^(3b), —(C₁-C₆ alkylenyl)-G^(3a), or            —(C₁-C₆ alkylenyl)-G^(3a)-G^(3b); and        -   R⁴ is R^(1a) or G⁴;    -   (iv) R^(x1) is —CN, -G^(x1)-G^(x2), —(C₁-C₆        alkylenyl)-G^(x1)-G^(x2), —C(O)N(R^(xa))(R^(xb)), hydrogen,        C₂-C₆ alkenyl, C₂-C₆ alkynyl, —C(O)OR^(ax1),        —C(O)NR^(bx1)R^(cx1), —C(O)R^(dx1), —S(O)₂R^(dx1),        —S(O)₂NR^(bx1)R^(cx1), G^(x1), C₁-C₆ haloalkyl, or C₁-C₆ alkyl;        wherein the C₁-C₆ alkyl, C₂-C₆ alkenyl, and C₂-C₆ alkynyl are        each optionally substituted with one substituent selected from        the group consisting of —CN, —OR^(xc), —SR^(xc), —S(O)R^(xc),        —S(O)₂R^(xc), —NR^(xa)R^(xc), —C(O)R^(xc), —C(O)OR^(xc),        —C(O)NR^(xa)R^(xc), —S(O)₂NR^(xa)R^(xc), and G^(x1);        -   G¹ is phenyl, C₃-C₆ cycloalkyl, C₅-C₆ heteroaryl, or C₄-C₆            heterocycle; wherein each G¹ is independently unsubstituted            or substituted with 1, 2, 3, 4, or 5 substituents            independently selected from the group consisting of R^(u)            and R^(v) groups;        -   R³ is R^(1a), —C(O)OH, —C(O)NR^(3a)R^(3b), —NR^(3a)R^(3b),            -G^(3a), -G^(3a)-G^(3b), —(C₁-C₆ alkylenyl)-OR^(3a), —(C₁-C₆            alkylenyl)-NR^(3a)R^(3b), —(C₁-C₆ alkylenyl)-G^(3a), or            —(C₁-C₆ alkylenyl)-G^(3a)-G^(3b); and        -   R⁴ is G⁴;    -   R^(xa), at each occurrence, is independently hydrogen, C₁-C₆        alkyl, or C₁-C₆ haloalkyl; R^(xb), at each occurrence, is        independently C₁-C₆ alkyl substituted with one substituent        selected from the group consisting of —CN, —OR^(ax1), —SR^(ax1),        —S(O)R^(dx1), —S(O)₂R^(dx1), —NR^(bx1)R^(cx1), —C(O)R^(ax1),        —C(O)OR^(ax1), —C(O)NR^(bx1)R^(cx1), and —S(O)₂NR^(bx1)R^(cx1);    -   R^(xc), at each occurrence, is independently hydrogen, C₁-C₆        alkyl, C₁-C₆ haloalkyl, G^(a), —(C₁-C₆ alkylenyl)-G^(a), or        R^(xb);    -   R^(ax1), R^(bx1), and R^(cx1), at each occurrence, are each        independently hydrogen, C₁-C₆ alkyl, C₁-C₆ haloalkyl, G^(a), or        —(C₁-C₆ alkylenyl)-G^(a);    -   R^(dx1), at each occurrence, is independently C₁-C₆ alkyl, C₁-C₆        haloalkyl, G^(a), or —(C₁-C₆ alkylenyl)-G^(a);    -   R^(1a), at each occurrence, is independently hydrogen, C₁-C₆        alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, halogen, C₁-C₆ haloalkyl,        CN, or NO₂;    -   R^(3a) and R^(3b), at each occurrence, are each independently        hydrogen, C₁-C₆ alkyl, C₁-C₆ haloalkyl, G^(3a), -G^(3a)-G^(3b),        —(C₁-C₆ alkylenyl)-G^(3a), —(C₁-C₆ alkylenyl)-G^(3a)-G^(3b), or        C₁-C₆ alkyl substituted with one substituents selected from the        group consisting of —CN, —OR^(h), —SR^(h), —S(O)R^(i),        —S(O)₂R^(h), —NR^(j)R^(k), —C(O)R^(h), —C(O)OR^(h),        —C(O)NR^(j)R^(k), and —S(O)₂NR^(j)R^(k);    -   G⁴, at each occurrence, is independently phenyl, C₃-C₆        cycloalkyl, C₅-C₆ heteroaryl, or C₄-C₆ heterocycle; each of        which is optionally substituted with 1, 2, 3, 4, or 5        substituents independently selected from the group consisting of        C₁-C₆ alkyl, NO₂, halogen, C₁-C₆ haloalkyl, —CN, oxo, —OR^(h),        —SR^(h), —S(O)₂R^(h), and —NR^(j)R^(k);    -   R^(u), at each occurrence, is independently —(C₁-C₆        alkylenyl)-G^(u), —(C₂-C₆ alkynylene)-G^(u), —(C₁-C₆        alkylenyl)-SR^(h), —C(O)—Z¹, —C(O)—NZ¹Z², —S(O)₂—Z¹, —N(Z²)Z¹,        or —N(Z²)S(O)₂—Z¹; wherein Z¹ is G^(u), —(C₁-C₆        alkylenyl)-G^(u), —(C₂-C₆ alkenylene)-G^(u), —(C₁-C₆        alkylenyl)-CN, —(C₁-C₆ alkylenyl)-SR^(h), —(C₁-C₆        alkylenyl)-OR^(h), —(C₁-C₆ alkylenyl)-NR^(j)R^(k), or —(C₁-C₆        alkylenyl)-C₁-C₄ alkoxy-C₁-C₄ alkoxy, and Z² is hydrogen, C₁-C₆        alkyl, or C₁-C₆ haloalkyl;    -   G^(u), at each occurrence, is independently aryl, heteroaryl,        heterocycle, cycloalkyl, or cycloalkenyl, wherein each G^(u) is        independently unsubstituted or substituted with 1, 2, 3, 4, or 5        substituents independently selected from the group consisting of        C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, halogen, C₁-C₆        haloalkyl, —CN, oxo, NO₂, —OR^(h), —O—(C₂-C₆        alkylenyl)-NR^(j)R^(k), —OC(O)R^(i), —OC(O)NR^(j)R^(k),        —O—(C₁-C₆ alkylenyl)-NR^(j)R^(k), —SR^(h), —S(O)₂R^(h),        —S(O)₂NR^(j)R^(k), —C(O)R^(h), —C(O)OR^(h), —C(O)NR^(j)R^(k),        —NR^(j)R^(k), —N(R^(h))C(O)R^(i), —N(R^(h))S(O)₂R^(i),        —N(R^(h))C(O)O(R^(i)), —N(R^(h))C(O)NR^(j)R^(k), G^(ua), —(C₁-C₆        alkylenyl)-OR^(h), —(C₁-C₆ alkylenyl)-OC(O)R^(i), —(C₁-C₆        alkylenyl)-OC(O)NR^(j)R^(k), —(C₁-C₆ alkylenyl)-SR^(h), —(C₁-C₆        alkylenyl)-S(O)₂R^(h), —(C₁-C₆ alkylenyl)-S(O)₂NR^(j)R^(k),        —(C₁-C₆ alkylenyl)-C(O)R^(h), —(C₁-C₆ alkylenyl)-C(O)OR^(h),        —(C₁-C₆ alkylenyl)-C(O)NR^(j)R^(k), —(C₁-C₆        alkylenyl)-NR^(j)R^(k), —(C₁-C₆ alkylenyl)-N(R^(h))C(O)R^(i),        —(C₁-C₆ alkylenyl)-N(R^(h))S(O)₂R^(i), —(C₁-C₆        alkylenyl)-N(R^(h))C(O)O(R^(i)), —(C₁-C₆        alkylenyl)-N(R^(h))C(O)NR^(j)R^(k), —(C₁-C₆ alkylenyl)-CN, and        —(C₁-C₆ alkylenyl)-G^(ua);    -   G^(a), G^(x1), G^(x2), G^(3a), G^(3b), and G^(ua), at each        occurrence, are each independently aryl, heteroaryl,        heterocycle, cycloalkyl, or cycloalkenyl, each of which is        optionally substituted with 1, 2, 3, 4, or 5 R^(z) groups;    -   R^(z) and R^(v), at each occurrence, are each independently        C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, halogen, C₁-C₆        haloalkyl, —CN, oxo, NO₂, —OR^(h), —OC(O)R^(i),        —OC(O)NR^(j)R^(k), —SR^(h), —S(O)₂R^(h), —S(O)₂NR^(j)R^(k),        —C(O)R^(h), —C(O)OR^(h), —C(O)NR^(j)R^(k), —NR^(j)R^(k),        —N(R^(h))C(O)R^(i), —N(R^(h))S(O)₂R^(i), —N(R^(h))C(O)O(R^(i)),        —N(R^(h))C(O)NR^(j)R^(k), —(C₁-C₆ alkylenyl)-OR^(h), —(C₁-C₆        alkylenyl)-OC(O)R^(i), —(C₁-C₆ alkylenyl)-OC(O)NR^(j)R^(k),        —(C₁-C₆ alkylenyl)-SR^(h), —(C₁-C₆ alkylenyl)-S(O)₂R^(h),        —(C₁-C₆ alkylenyl)-S(O)₂NR^(j)R^(k), —(C₁-C₆        alkylenyl)-C(O)R^(h), —(C₁-C₆ alkylenyl)-C(O)OR^(h), —(C₁-C₆        alkylenyl)-C(O)NR^(j)R^(k), —(C₁-C₆ alkylenyl)-NR^(j)R^(k),        —(C₁-C₆ alkylenyl)-N(R^(h))C(O)R^(i), —(C₁-C₆        alkylenyl)-N(R^(h))S(O)₂R^(i), —(C₁-C₆        alkylenyl)-N(R^(h))C(O)O(R^(i)), —(C₁-C₆        alkylenyl)-N(R^(h))C(O)NR^(j)R^(k), or —(C₁-C₆ alkylenyl)-CN;    -   R^(h), R^(j), R^(k), at each occurrence, are each independently        hydrogen, C₁-C₆ alkyl, or C₁-C₆ haloalkyl; and    -   R^(i), at each occurrence, is independently C₁-C₆ alkyl or C₁-C₆        haloalkyl.

In another aspect, the present invention provides for methods fortreating or preventing disorders that are ameliorated by inhibition ofBET. Such methods comprise of administering to the subject atherapeutically effective amount of a compound of formula (I), or apharmaceutically acceptable salt thereof, alone, or in combination witha pharmaceutically acceptable carrier.

Some of the methods are directed to treating or preventing aninflammatory disease or cancer or AIDS.

In another aspect, the present invention relates to methods of treatingcancer in a subject comprising administering a therapeutically effectiveamount of a compound of formula (I) or a pharmaceutically acceptablesalt thereof, to a subject in need thereof. In certain embodiments, thecancer is selected from the group consisting of: acoustic neuroma, acuteleukemia, acute lymphocytic leukemia, acute myelocytic leukemia(monocytic, myeloblastic, adenocarcinoma, angiosarcoma, astrocytoma,myelomonocytic and promyelocytic), acute t-cell leukemia, basal cellcarcinoma, bile duct carcinoma, bladder cancer, brain cancer, breastcancer, bronchogenic carcinoma, cervical cancer, chondrosarcoma,chordoma, choriocarcinoma, chronic leukemia, chronic lymphocyticleukemia, chronic myelocytic (granulocytic) leukemia, chronicmyelogenous leukemia, colon cancer, colorectal cancer,craniopharyngioma, cystadenocarcinoma, diffuse large B-cell lymphoma,dysproliferative changes (dysplasias and metaplasias), embryonalcarcinoma, endometrial cancer, endotheliosarcoma, ependymoma, epithelialcarcinoma, erythroleukemia, esophageal cancer, estrogen-receptorpositive breast cancer, essential thrombocythemia, Ewing's tumor,fibrosarcoma, follicular lymphoma, germ cell testicular cancer, glioma,glioblastoma, gliosarcoma, heavy chain disease, hemangioblastoma,hepatoma, hepatocellular cancer, hormone insensitive prostate cancer,leiomyosarcoma, leukemia, liposarcoma, lung cancer,lymphagioendotheliosarcoma, lymphangiosarcoma, lymphoblastic leukemia,lymphoma (Hodgkin's and non-Hodgkin's), malignancies andhyperproliferative disorders of the bladder, breast, colon, lung,ovaries, pancreas, prostate, skin and uterus, lymphoid malignancies ofT-cell or B-cell origin, leukemia, lymphoma, medullary carcinoma,medulloblastoma, melanoma, meningioma, mesothelioma, multiple myeloma,myelogenous leukemia, myeloma, myxosarcoma, neuroblastoma, NUT midlinecarcinoma (NMC), non-small cell lung cancer, oligodendroglioma, oralcancer, osteogenic sarcoma, ovarian cancer, pancreatic cancer, papillaryadenocarcinomas, papillary carcinoma, pinealoma, polycythemia vera,prostate cancer, rectal cancer, renal cell carcinoma, retinoblastoma,rhabdomyosarcoma, sarcoma, sebaceous gland carcinoma, seminoma, skincancer, small cell lung carcinoma, solid tumors (carcinomas andsarcomas), small cell lung cancer, stomach cancer, squamous cellcarcinoma, synovioma, sweat gland carcinoma, thyroid cancer,Waldenström's macroglobulinemia, testicular tumors, uterine cancer andWilms' tumor. In certain embodiments, the methods further compriseadministering a therapeutically effective amount of at least oneadditional therapeutic agent. In certain embodiments, the additionaltherapeutic agent is selected from the group consisting of cytarabine,bortezomib, and 5-azacitidine.

In another aspect, the present invention relates to methods of treatinga disease or condition in a subject comprising administering atherapeutically effective amount of a compound of formula (I) or apharmaceutically acceptable salt thereof, to a subject in need thereof,wherein said disease or condition is selected from the group consistingof: Addison's disease, acute gout, ankylosing spondylitis, asthma,atherosclerosis, Behcet's disease, bullous skin diseases, cardiacmyopathy, cardiac hypertrophy, chronic obstructive pulmonary disease(COPD), Crohn's disease, dermatitis, eczema, giant cell arteritis,glomerulonephritis, heart failure, hepatitis, hypophysitis, inflammatorybowel disease, Kawasaki disease, lupus nephritis, multiple sclerosis,myocarditis, myositis, nephritis, organ transplant rejection,osteoarthritis, pancreatitis, pericarditis, Polyarteritis nodosa,pneumonitis, primary biliary cirrhosis, psoriasis, psoriatic arthritis,rheumatoid arthritis, scleritis, sclerosing cholangitis, sepsis,systemic lupus erythematosus, Takayasu's Arteritis, toxic shock,thyroiditis, type I diabetes, ulcerative colitis, uveitis, vitiligo,vasculitis, and Wegener's granulomatosis. In certain embodiments, themethods further comprise administering a therapeutically effectiveamount of at least one additional therapeutic agent.

In another aspect, the present invention relates to methods of treatinga chronic kidney disease or condition in a subject comprisingadministering a therapeutically effective amount of a compound offormula (I) or a pharmaceutically acceptable salt thereof, to a subjectin need thereof, wherein said disease or condition is selected from thegroup consisting of: diabetic nephropathy, hypertensive nephropathy,HIV-associated nephropathy, glomerulonephritis, lupus nephritis, IgAnephropathy, focal segmental glomerulosclerosis, membranousglomerulonephritis, minimal change disease, polycystic kidney diseaseand tubular interstitial nephritis. In certain embodiments, the methodsfurther comprise administering a therapeutically effective amount of atleast one additional therapeutic agent.

In another aspect, the present invention relates to methods of treatingan acute kidney injury or disease or condition in a subject comprisingadministering a therapeutically effective amount of a compound offormula (I) or a pharmaceutically acceptable salt thereof, to a subjectin need thereof, wherein said acute kidney injury or disease orcondition is selected from the group consisting of: ischemia-reperfusioninduced, cardiac and major surgery induced, percutaneous coronaryintervention induced, radio-contrast agent induced, sepsis induced,pneumonia induced, and drug toxicity induced. In certain embodiments,the methods further comprise administering a therapeutically effectiveamount of at least one additional therapeutic agent.

In another aspect, the present invention relates to methods of treatingAIDS in a subject comprising administering a therapeutically effectiveamount of a compound of formula (I) or a pharmaceutically acceptablesalt thereof, to a subject in need thereof. In certain embodiments, themethods further comprise administering a therapeutically effectiveamount of at least one additional therapeutic agent.

In another aspect, the present invention relates to methods of treatingobesity, dyslipidemia, hypercholesterolemia, Alzheimer's disease,metabolic syndrome, hepatic steatosis, type II diabetes, insulinresistance, diabetic retinopathy or diabetic neuropathy in a subjectcomprising administering a therapeutically effective amount of acompound of formula (I) or a pharmaceutically acceptable salt thereof,to a subject in need thereof. In certain embodiments, the methodsfurther comprise administering a therapeutically effective amount of atleast one additional therapeutic agent.

In another aspect, the present invention relates to methods ofpreventing conception by inhibiting spermatogenesis in a subjectcomprising administering a therapeutically effective amount of acompound of formula (I) or a pharmaceutically acceptable salt thereof,to a subject in need thereof. In certain embodiments, the methodsfurther comprise administering a therapeutically effective amount of atleast one additional therapeutic agent.

A further aspect of the invention provides the use of a compound offormula (I), alone or in combination with at least one additionaltherapeutic agent, in the manufacture of a medicament for treating orpreventing conditions and disorders disclosed herein, and with orwithout a pharmaceutically acceptable carrier.

Pharmaceutical compositions comprising a compound of formula (I), or apharmaceutically acceptable salt, alone or in combination with at leastone additional therapeutic agent, are also provided.

DETAILED DESCRIPTION

Disclosed herein are compounds of formula (I)

wherein R^(x), R^(y), R^(x1), A¹, A², A³, A⁴, L¹ and G¹ are definedabove in the Summary of the Invention and below in the DetailedDescription. Further, compositions comprising such compounds and methodsfor treating conditions and disorders using such compounds andcompositions are also disclosed.

Compounds disclosed herein may contain one or more variable(s) thatoccur more than one time in any substituent or in the formulae herein.Definition of a variable on each occurrence is independent of itsdefinition at another occurrence. Further, combinations of substituentsare permissible only if such combinations result in stable compounds.Stable compounds are compounds, which can be isolated from a reactionmixture.

Definitions

It is noted that, as used in this specification and the intended claims,the singular form “a,” “an,” and “the” include plural referents unlessthe context clearly dictates otherwise. Thus, for example, reference to“a compound” includes a single compound as well as one or more of thesame or different compounds, reference to “optionally a pharmaceuticallyacceptable carrier” refers to a single optional pharmaceuticallyacceptable carrier as well as one or more pharmaceutically acceptablecarriers, and the like.

As used in the specification and the appended claims, unless specifiedto the contrary, the following terms have the meaning indicated:

The term “alkenyl” as used herein, means a straight or branchedhydrocarbon chain containing from 2 to 10 carbons and containing atleast one carbon-carbon double bond. The term “C₂-C₆ alkenyl” means analkenyl group containing 2-6 carbon atoms. Non-limiting examples ofalkenyl include buta-1,3-dienyl, ethenyl, 2-propenyl,2-methyl-2-propenyl, 3-butenyl, 4-pentenyl, and 5-hexenyl.

The term “C₂-C₆ alkenylene” means a divalent group derived from astraight or branched chain hydrocarbon of 2 to 6 carbon atoms andcontains at least one carbon-carbon double bond. Representative examplesof C₂-C₆ alkenylene include, but are not limited to, —CH═CH— and—CH₂CH═CH—.

The term “alkyl” as used herein, means a saturated, straight or branchedhydrocarbon chain radical. In some instances, the number of carbon atomsin an alkyl moiety is indicated by the prefix “C_(x)-C_(y)”, wherein xis the minimum and y is the maximum number of carbon atoms in thesubstituent. Thus, for example, “C₁-C₆ alkyl” refers to an alkylsubstituent containing from 1 to 6 carbon atoms and “C₁-C₃ alkyl” refersto an alkyl substituent containing from 1 to 3 carbon atoms.Representative examples of alkyl include, but are not limited to,methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, iso-butyl,tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, 1-methylbutyl,2-methylbutyl, 3-methylbutyl, 3,3-dimethylbutyl, 1,1-dimethylpropyl,1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-methylpropyl, 2-methylpropyl,1-ethylpropyl, 1,2,2-trimethylpropyl, 3-methylhexyl, 2,2-dimethylpentyl,2,3-dimethylpentyl, n-heptyl, n-octyl, n-nonyl, and n-decyl.

The term “alkylene” or “alkylenyl” means a divalent radical derived froma straight or branched, saturated hydrocarbon chain, for example, of 1to 10 carbon atoms or of 1 to 6 carbon atoms (C₁-C₆ alkylenyl) or of 1to 4 carbon atoms or of 1 to 3 carbon atoms (C₁-C₃ alkylenyl) or of 2 to6 carbon atoms (C₂-C₆ alkylenyl). Examples of alkylene and alkylenylinclude, but are not limited to, —CH₂—, —CH₂CH₂—, —C(CH₃)₂)—CH₂CH₂CH₂—,—CH₂CH₂CH₂CH₂—, and —CH₂CH(CH₃)CH₂—.

The term “C₂-C₆ alkynyl” as used herein, means a straight or branchedchain hydrocarbon radical containing from 2 to 6 carbon atoms andcontaining at least one carbon-carbon triple bond. Representativeexamples of C₂-C₆ alkynyl include, but are not limited, to acetylenyl,1-propynyl, 2-propynyl, 3-butynyl, 2-pentynyl, and 1-butynyl.

The term “C₂-C₆ alkynylene” means a divalent group derived from astraight or branched chain hydrocarbon of from 2 to 6 carbon atomscontaining at least one triple bond. Representative examples ofalkynylene include, but are not limited to, —C≡C—, —CH₂C≡C—,—CH(CH₃)CH₂C≡C—, —C≡CCH₂—, and —C≡CCH(CH₃)CH₂—.

The term “C₁-C₄ alkoxy” as used herein, means a C₁-C₄ alkyl group, asdefined herein, appended to the parent molecular moiety through anoxygen atom. Representative examples of C₁-C₄ alkoxy include, but arenot limited to, methoxy, ethoxy, propoxy, 2-propoxy, and butoxy.

The term “aryl” as used herein, means phenyl or a bicyclic aryl. Thebicyclic aryl is naphthyl, or a phenyl fused to a monocyclic cycloalkyl,or a phenyl fused to a monocyclic cycloalkenyl. Non-limiting examples ofthe aryl groups include dihydroindenyl, indenyl, naphthyl,dihydronaphthalenyl, and tetrahydronaphthalenyl. The bicyclic aryls areattached to the parent molecular moiety through any carbon atomcontained within the bicyclic ring systems.

The term “cycloalkyl” as used herein, refers to a radical that is amonocyclic cyclic alkyl, a bicyclic cycloalkyl, or a spiro cycloalkyl.The monocyclic cycloalkyl is a carbocyclic ring system containing threeto eight carbon atoms, zero heteroatoms and zero double bonds. Examplesof monocyclic ring systems include cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl, cycloheptyl, and cyclooctyl. The bicyclic cycloalkyl is amonocyclic cycloalkyl fused to a monocyclic cycloalkyl ring. Themonocyclic and the bicyclic cycloalkyl groups may contain one or twoalkylene bridges, each consisting of one, two, three, or four carbonatoms in length, and each bridge links two non-adjacent carbon atoms ofthe ring system. Non-limiting examples of bicyclic ring systems includebicyclo[3.1.1]heptane, bicyclo[2.2.1]heptane, bicyclo[2.2.2]octane,bicyclo[3.2.2]nonane, bicyclo[3.3.1]nonane, and bicyclo[4.2.1]nonane,tricyclo[3.3.1.0^(3,7)]nonane (octahydro-2,5-methanopentalene ornoradamantane), and tricyclo[3.3.1.1^(3,7)]decane (adamantane). A spirocycloalkyl is a monocyclic cycloalkyl wherein two substituents on thesame carbon atom of the monocyclic cycloalkyl ring together with saidcarbon atom form a second monocyclic cycloalkyl ring. The monocyclic,the bicyclic, and the spiro cycloalkyl groups are attached to the parentmolecular moiety through any substitutable atom contained within thering system.

The term “C₃-C₆ cycloalkyl” as used herein, means cyclopropyl,cyclobutyl, cyclopentyl, and cyclohexyl.

The term “cycloalkenyl” as used herein, refers to a monocyclic or abicyclic hydrocarbon ring radical. The monocyclic cycloalkenyl hasfour-, five-, six-, seven- or eight carbon atoms and zero heteroatoms.The four-membered ring systems have one double bond, the five- orsix-membered ring systems have one or two double bonds, and the seven-or eight-membered ring systems have one, two, or three double bonds.Representative examples of monocyclic cycloalkenyl groups include, butare not limited to, cyclobutenyl, cyclopentenyl, cyclohexenyl,cycloheptenyl, and cyclooctenyl. The bicyclic cycloalkenyl is amonocyclic cycloalkenyl fused to a monocyclic cycloalkyl group, or amonocyclic cycloalkenyl fused to a monocyclic cycloalkenyl group. Themonocyclic or bicyclic cycloalkenyl ring may contain one or two alkylenebridges, each consisting of one, two, or three carbon atoms, and eachlinking two non-adjacent carbon atoms of the ring system. Representativeexamples of the bicyclic cycloalkenyl groups include, but are notlimited to, 4,5,6,7-tetrahydro-3aH-indene, octahydronaphthalenyl, and1,6-dihydro-pentalene. The monocyclic and bicyclic cycloalkenyls can beattached to the parent molecular moiety through any substitutable atomcontained within the ring systems.

The term “C₅-C₈ cycloalkenyl” as used herein, means a cyclohexenyl,cyclohexadienyl, cyclopentenyl, cycloheptenyl, and cyclooctenyl. TheC₅-C₈ cycloalkenyls can be attached to the parent molecular moietythrough any substitutable atom contained within the ring systems.

The term “halo” or “halogen” as used herein, means Cl, Br, I, and F.

The term “haloalkyl” as used herein, means an alkyl group, as definedherein, in which one, two, three, four, five or six hydrogen atoms arereplaced by halogen. The term “C₁-C₆ haloalkyl” means a C₁-C₆ alkylgroup, as defined herein, in which one, two, three, four, five, or sixhydrogen atoms are replaced by halogen. The term “C₁-C₃ haloalkyl” meansa C₁-C₃ alkyl group, as defined herein, in which one, two, or threehydrogen atoms are replaced by halogen. Representative examples ofhaloalkyl include, but are not limited to, chloromethyl, 2-fluoroethyl,2,2-difluoroethyl, 2,2,2-trifluoroethyl, trifluoromethyl,difluoromethyl, pentafluoroethyl, 2-chloro-3-fluoropentyl,trifluorobutyl, and trifluoropropyl.

The term “heterocycle” or “heterocyclic” as used herein, means a radicalof a monocyclic heterocycle, a bicyclic heterocycle, and a spiroheterocycle. A monocyclic heterocycle is a three-, four-, five-, six-,seven-, or eight-membered carbocyclic ring also containing at least oneheteroatom independently selected from the group consisting of O, N, andS. A three- or four-membered ring contains zero or one double bond, andone heteroatom selected from the group consisting of O, N, and S. Whentwo O atoms or one O atom and one S atom are present in a heterocyclicring, then the two O atoms or one O atom and one S atom are not bondeddirectly to each other. A five-membered ring contains zero or one doublebond and one, two, or three heteroatoms selected from the groupconsisting of O, N, and S. Examples of five-membered heterocyclic ringsinclude those containing in the ring: 1O; 1S; 1N; 2N; 3N; 1S and 1N; 1S,and 2N; 1O and 1N; or 1O and 2N. Examples of 5-membered heterocyclicgroups include tetrahydrofuranyl, dihydrofuranyl, tetrahydrothienyl,dihydrothienyl, imidazolidinyl, oxazolidinyl, imidazolinyl,isoxazolidinyl, pyrrolidinyl, 2-pyrrolinyl, and 3-pyrrolinyl. Asix-membered ring contains zero, one, or two double bonds and one, two,or three heteroatoms selected from the group consisting of O, N, and S.Examples of six-membered heterocyclic rings include those containing inthe ring: 1O; 2O; 1S; 2S; 1N; 2N; 3N; 1S, 1O, and 1N; 1S and 1N; 1S and2N; 1S and 1O; 1S and 2O; 1Q and 1N; and 1O and 2N. Examples of6-membered heterocyclic groups include tetrahydropyranyl,dihydropyranyl, dioxanyl, 1,3-dioxolanyl, 1,4-dithianyl,hexahydropyrimidine, morpholinyl, piperazinyl, piperidinyl, 2H-pyranyl,4H-pyranyl, pyrazolidinyl, pyrazolinyl, 1,2,3,6-tetrahydropyridinyl,tetrahydrothiopyranyl, 1,1-dioxo-hexahydro-1-thiopyranyl,1,1-dioxo-1λ⁶-thiomorpholinyl, thiomorpholinyl, thioxanyl, andtrithianyl. Seven- and eight-membered rings contains zero, one, two, orthree double bonds and one, two, or three heteroatoms selected from thegroup consisting of O, N, and S. Representative examples of monocyclicheterocycles include, but are not limited to, azetidinyl, azepanyl,aziridinyl, diazepanyl, 1,3-dioxanyl, 1,3-dioxolanyl, 1,3-dithiolanyl,1,3-dithianyl, imidazolinyl, imidazolidinyl, isothiazolinyl,isothiazolidinyl, isoxazolinyl, isoxazolidinyl, morpholinyl,oxadiazolinyl, oxadiazolidinyl, oxazolinyl, oxazolidinyl, oxetanyl,piperazinyl, piperidinyl, pyranyl, pyrazolinyl, pyrazolidinyl,pyrrolinyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydropyridinyl,tetrahydropyranyl, tetrahydrothienyl, thiadiazolinyl, thiadiazolidinyl,thiazolinyl, thiazolidinyl, thiomorpholinyl, thiopyranyl, andtrithianyl. The bicyclic heterocycle is a monocyclic heterocycle fusedto a phenyl group, or a monocyclic heterocycle fused to a monocycliccycloalkyl, or a monocyclic heterocycle fused to a monocycliccycloalkenyl, or a monocyclic heterocycle fused to a monocyclicheterocycle. Representative examples of bicyclic heterocycles include,but are not limited to, benzopyranyl, benzothiopyranyl,2,3-dihydrobenzofuranyl, 2,3-dihydrobenzothienyl,2,3-dihydro-1H-indolyl, 3,4-dihydroisoquinolin-2(1H)-yl,2,3,4,6-tetrahydro-1H-pyrido[1,2-a]pyrazin-2-yl,hexahydropyrano[3,4-b][1,4]oxazin-1 (5H)-yl. The monocyclic heterocycleand the bicyclic heterocycle may contain one or two alkylene bridges oran alkenylene bridge, or mixture thereof, each consisting of no morethan four carbon atoms and each linking two non adjacent atoms of thering system. Examples of such bridged heterocycle include, but are notlimited to, azabicyclo[2.2.1]heptyl (including2-azabicyclo[2.2.1]hept-2-yl), 8-azabicyclo[3.2.1]oct-8-yl,octahydro-2,5-epoxypentalene,hexahydro-2H-2,5-methanocyclopenta[b]furan,hexahydro-1H-1,4-methanocyclopenta[c]furan, aza-admantane(1-azatricyclo[3.3.1.1^(3,7)]decane), and oxa-adamantane(2-oxatricyclo[3.3.1.1^(3,7)]decane). A spiro heterocycle is amonocyclic heterocycle wherein two substituents on the same carbon atomof the monocyclic heterocycle ring together with said carbon atom form asecond ring system selected from a monocyclic cycloalkyl, a bicycliccycloalkyl, a monocyclic heterocycle, or a bicyclic heterocycle.Examples of spiro heterocycle include, but not limited to,6-azaspiro[2.5]oct-6-yl, 1′H,4H-spiro[1,3-benzodioxine-2,4′-piperidin]-1′-yl, 1′H,3H-spiro[2-benzofuran-1,4′-piperidin]-1′-yl, and1,4-dioxa-8-azaspiro[4.5]dec-8-yl. The monocyclic, the bicyclic, and thespiro heterocycles can be unsubstituted or substituted. The monocyclic,the bicyclic and the spiro heterocycles are connected to the parentmolecular moiety through any carbon atom or any nitrogen atom containedwithin the ring systems. The nitrogen and sulfur heteroatoms in theheterocycle rings may optionally be oxidized (e.g.1,1-dioxidotetrahydrothienyl, 1,1-dioxido-1,2-thiazolidinyl,1,1-dioxidothiomorpholinyl)) and the nitrogen atoms may optionally bequarternized.

The term “C₃-C₇ heterocycle” or “C₃-C₇ heterocyclic” as used herein,means a 3, 4, 5, 6 or 7 membered monocyclic heterocycle as definedherein above.

The term “C₄-C₆ heterocycle” or “C₄-C₆ heterocyclic” as used herein,means a 4, 5, or 6 membered monocyclic heterocycle as defined hereinabove. Examples of C₄-C₆ heterocycle include azetidinyl, pyrrolidinyl,1,2-thiazolidinyl, tetrahydrofuranyl, tetrahydropyranyl, piperazinyl,piperidinyl, pyridin-1(2H)-yl, thiomorpholinyl, and morpholinyl.

The term “heteroaryl” as used herein, means a monocyclic heteroaryl anda bicyclic heteroaryl. The monocyclic heteroaryl is a five- orsix-membered ring. The five-membered ring contains two double bonds. Thefive membered ring may contain one heteroatom selected from O or S; orone, two, three, or four nitrogen atoms and optionally one oxygen or onesulfur atom. The six-membered ring contains three double bonds and one,two, three or four nitrogen atoms. Representative examples of monocyclicheteroaryl include, but are not limited to, furanyl, imidazolyl,isoxazolyl, isothiazolyl, oxadiazolyl, 1,3-oxazolyl, pyridinyl,pyridazinyl, pyrimidinyl, pyrazinyl, pyrazolyl, pyrrolyl, tetrazolyl,thiadiazolyl, 1,3-thiazolyl, thienyl, triazolyl, and triazinyl. Thebicyclic heteroaryl consists of a monocyclic heteroaryl fused to aphenyl, or a monocyclic heteroaryl fused to a monocyclic cycloalkyl, ora monocyclic heteroaryl fused to a monocyclic cycloalkenyl, or amonocyclic heteroaryl fused to a monocyclic heteroaryl, or a monocyclicheteroaryl fused to a monocyclic heterocycle. Representative examples ofbicyclic heteroaryl groups include, but are not limited to,benzofuranyl, benzothienyl, benzoxazolyl, benzimidazolyl,benzoxadiazolyl, phthalazinyl,2,6-dihydropyrrolo[3,4-c]pyrazol-5(4H)-yl,6,7-dihydro-pyrazolo[1,5-a]pyrazin-5(4H)-yl,6,7-dihydro-1,3-benzothiazolyl, imidazo[1,2-a]pyridinyl, indazolyl,indolyl, isoindolyl, isoquinolinyl, naphthyridinyl, pyridoimidazolyl,quinolinyl, 2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridin-5-yl,thiazolo[5,4-b]pyridin-2-yl, thiazolo[5,4-d]pyrimidin-2-yl, and5,6,7,8-tetrahydroquinolin-5-yl. The monocyclic and bicyclic heteroarylgroups are connected to the parent molecular moiety through anysubstitutable carbon atom or any substitutable nitrogen atom containedwithin the ring systems. The nitrogen atom in the heteroaryl rings mayoptionally be oxidized and may optionally be quarternized.

The term “C₅-C₆ heteroaryl” as used herein, means a 5- or 6-memberedmonocyclic heteroaryl ring as described above. Examples of C₅-C₆heteroaryl include furanyl, thienyl, pyrazolyl, imidazolyl,1,2,4-oxadiazolyl, 1,2,4-triazolyl, 1,3-thiazolyl, pyridinyl,pyrimidinyl, and pyrazinyl.

The term “heteroatom” as used herein, means a nitrogen, oxygen, andsulfur.

The term “oxo” as used herein, means a ═O group.

If a moiety is described as “substituted”, a non-hydrogen radical is inthe place of hydrogen radical of any substitutable atom of the moiety.Thus, for example, a substituted heterocycle moiety is a heterocyclemoiety in which at least one non-hydrogen radical is in the place of ahydrogen radical on the heterocycle. It should be recognized that ifthere are more than one substitution on a moiety, each non-hydrogenradical may be identical or different (unless otherwise stated).

If a moiety is described as being “optionally substituted,” the moietymay be either (1) not substituted or (2) substituted. If a moiety isdescribed as being optionally substituted with up to a particular numberof non-hydrogen radicals, that moiety may be either (1) not substituted;or (2) substituted by up to that particular number of non-hydrogenradicals or by up to the maximum number of substitutable positions onthe moiety, whichever is less. Thus, for example, if a moiety isdescribed as a heteroaryl optionally substituted with up to 3non-hydrogen radicals, then any heteroaryl with less than 3substitutable positions would be optionally substituted by up to only asmany non-hydrogen radicals as the heteroaryl has substitutablepositions. To illustrate, tetrazolyl (which has only one substitutableposition) would be optionally substituted with up to one non-hydrogenradical. To illustrate further, if an amino nitrogen is described asbeing optionally substituted with up to 2 non-hydrogen radicals, then aprimary amino nitrogen will be optionally substituted with up to 2non-hydrogen radicals, whereas a secondary amino nitrogen will beoptionally substituted with up to only 1 non-hydrogen radical.

The terms “treat”, “treating”, and “treatment” refer to a method ofalleviating or abrogating a disease and/or its attendant symptoms.

The terms “prevent”, “preventing”, and “prevention” refer to a method ofpreventing the onset of a disease and/or its attendant symptoms orbarring a subject from acquiring a disease. As used herein, “prevent”,“preventing” and “prevention” also include delaying the onset of adisease and/or its attendant symptoms and reducing a subject's risk ofacquiring a disease.

The phrase “therapeutically effective amount” means an amount of acompound, or a pharmaceutically acceptable salt thereof, sufficient toprevent the development of or to alleviate to some extent one or more ofthe symptoms of the condition or disorder being treated whenadministered alone or in conjunction with another therapeutic agent ortreatment in a particular subject or subject population. For example ina human or other mammal, a therapeutically effective amount can bedetermined experimentally in a laboratory or clinical setting, or may bethe amount required by the guidelines of the United States Food and DrugAdministration, or equivalent foreign agency, for the particular diseaseand subject being treated.

The term “subject” is defined herein to refer to animals such asmammals, including, but not limited to, primates (e.g., humans), cows,sheep, goats, horses, dogs, cats, rabbits, rats, mice and the like. Inpreferred embodiments, the subject is a human.

Compounds

Compounds of the invention have the general formula (I) as describedabove.

Particular values of variable groups in compounds of formula (I) are asfollows. Such values may be used where appropriate with any of the othervalues, definitions, claims or embodiments defined hereinbefore orhereinafter.

In certain embodiments of formula (I), R^(x) is hydrogen or C₁-C₃ alkyl.

In certain embodiments, R^(x) is hydrogen.

In certain embodiments, R^(x) is C₁-C₃ alkyl. In some such embodiments,R^(x) is methyl.

In certain embodiments of formula (I), R^(y) is hydrogen or C₁-C₃ alkyl.

In certain embodiments, R^(y) is C₁-C₃ alkyl. In some such embodiments,R^(y) is methyl.

In certain embodiments, R^(y) is hydrogen.

In certain embodiments of formula (I), A¹ is N or CR¹, A² is N or CR²,A³ is N or CR³; and A⁴ is N or CR⁴; wherein zero, one, two, or three ofA¹, A², A³, and A⁴ are N.

In certain embodiments, A¹ is CR¹, A² is CR², A³ is CR³; and A⁴ is CR⁴.

In certain embodiments, one of A¹, A², A³, and A⁴ is N.

In certain embodiments of formula (I), R¹ is hydrogen, C₁-C₆ alkyl,C₂-C₆ alkenyl, C₂-C₆ alkynyl, halogen, C₁-C₆ haloalkyl, CN, or NO₂.

In certain embodiments, R¹ is hydrogen.

In certain embodiments of formula (I), R² is hydrogen, —S(O)₂R^(2a),—S(O)₂NR^(2b)R^(2c), —N(R^(2b))S(O)₂R^(2a), or —(C₁-C₆alkylenyl)-S(O)₂R^(2a); wherein R^(2a) is C₁-C₆ alkyl or C₁-C₆haloalkyl; and R^(2b) and R^(2c) are each independently hydrogen, C₁-C₆alkyl, or C₁-C₆ haloalkyl.

In certain embodiments, R² is hydrogen, —S(O)₂R^(2a),—S(O)₂NR^(2b)R^(2c), —N(R^(2b))S(O)₂R^(2a), or —(C₁-C₃alkylenyl)-S(O)₂R^(2a). In some such embodiments, R^(2a) is C₁-C₃ alkyl;and R^(2b) and R^(2c) are each independently hydrogen or C₁-C₃ alkyl.

In certain embodiments, R² is hydrogen, —S(O)₂R^(2a), or—N(R^(2b))S(O)₂R^(2a). In some such embodiments, R^(2a) is C₁-C₃ alkyl;and R^(2b) is hydrogen.

In certain embodiments of formula (I), L¹ is O, N(H), or OCH₂ whereinthe CH₂ moiety of OCH₂ is attached to G¹.

In certain embodiments, L¹ is O or OCH₂.

In certain embodiments, L¹ is O.

In certain embodiments, L¹ is OCH₂.

In certain embodiments, L¹ is N(H).

In certain embodiments of formula (I), R^(x1), G¹, R³, and R⁴, areselected from (i), (ii), (iii), or (iv).

In certain embodiments, R^(x1), G¹, R³, and R⁴, are selected from (i).

In certain embodiments, R^(x1), G¹, R³, and R⁴, are selected from (i)wherein R^(x1) is -G^(x1)-G^(x2), —(C₁-C₆ alkylenyl)-G^(x1)-G^(x2),—C(O)N(R^(xa))(R^(xb)), C₂-C₆ alkenyl, or C₂-C₆ alkynyl; wherein theC₂-C₆ alkenyl and C₂-C₆ alkynyl are each independently substituted withone substituent selected from the group consisting of —CN, —OR^(xc),—SR^(xc), —S(O)R^(xc), —S(O)₂R^(xc), —NR^(xa)R^(xc), —C(O)R^(xc),—C(O)OR^(xc), —C(O)NR^(xa)R^(xc), —S(O)₂NR^(xa)R^(xc), and G^(x1).

In certain embodiments, R^(x1), G¹, R³, and R⁴, are selected from (i)wherein R^(x1) is —(C₁-C₆ alkylenyl)-G^(x1)-G^(x2), C₂-C₆ alkenyl, orC₂-C₆ alkynyl; wherein the C₂-C₆ alkenyl and C₂-C₆ alkynyl are eachindependently substituted with one substituent selected from the groupconsisting of —CN, —OR^(xc), —SR^(xc), —S(O)R^(xc), —S(O)₂R^(xc),—NR^(xa)R^(xc), —C(O)R^(xc), —C(O)OR^(xc), —C(O)NR^(xa)R^(xc),—S(O)₂NR^(xa)R^(xc), and G^(x1).

In certain embodiments, R^(x1), G¹, R³, and R⁴, are selected from (i)wherein R^(x1) is —(C₁-C₆ alkylenyl)-G^(x1)-G^(x2). In some suchembodiments, G^(x1) is optionally substituted C₄-C₆ heterocycle. In somesuch embodiments, G^(x1) is azetidinyl, pyrrolidinyl, piperazinyl,1,4-diazepanyl, morpholinyl, or piperidinyl; each of which is optionallysubstituted. In some such embodiments, G^(x1) is optionally substitutedpiperazinyl. In some such embodiments, G^(x2) is phenyl, C₃-C₆cycloalkyl, C₅-C₆ heteroaryl, or C₄-C₆ heterocycle, each of which isoptionally substituted.

In certain embodiments, R^(x1), G¹, R³, and R⁴, are selected from (i)wherein R^(x1) is -G^(x1)-G^(x2). In some such embodiments, G^(x1) isoptionally substituted C₅-C₆ heteroaryl. In some such embodiments,G^(x1) is pyrazolyl, 1,2,4-oxadiazolyl, or pyridinyl; each of which isoptionally substituted. In some such embodiments, G^(x2) is phenyl,C₅-C₆ heteroaryl, C₄-C₆ heterocycle, or C₃-C₆ cycloalkyl; each of whichis optionally substituted. In some such embodiments, G^(x2) is phenyl,thiazolyl, pyridinyl, pyrazinyl, cyclopropyl, cyclohexyl, piperidinyl,tetrahydropyranyl, or morpholinyl; each of which is optionallysubstituted.

In certain embodiments, R^(x1), G¹, R³, and R⁴, are selected from (i)wherein R^(x1) is —C(O)N(R^(xa))(R^(xb)). In some such embodiments,R^(xa) is hydrogen or C₁-C₃ alkyl. In some such embodiments, R^(xa) ishydrogen. In some such embodiments, R^(xb) is C₁-C₆ alkyl substitutedwith one substituent selected from the group consisting of —CN,—NR^(bx1)R^(cx1), —C(O)R^(ax1) and —C(O)NR^(bx1)R^(cx1). In some suchembodiments, R^(bx1) and R^(cx1) are each independently hydrogen orC₁-C₆ alkyl. In some such embodiments, R^(ax1) is optionally substitutedC₄-C₆ heterocycle.

In certain embodiments, R^(x1), G¹, R³, and R⁴, are selected from (i)wherein R^(x1) is C₂-C₆ alkenyl, wherein the C₂-C₆ alkenyl issubstituted with one substituent selected from the group consisting of—CN, —OR^(xc), —SR^(xc), —S(O)R^(xc), —S(O)₂R^(xc), —NR^(xa)R^(xc),—C(O)R^(xc), —C(O)OR^(xc), —C(O)NR^(xa)R^(xc), —S(O)₂NR^(xa)R^(xc), andG^(x1). In some such embodiments, the C₂-C₆ alkenyl is substituted withone —C(O)NR^(xa)R^(xc) group. In some such embodiments, the C₂-C₆alkenyl is substituted with one —NR^(xa)R^(xc) group. In some suchembodiments, R^(xa) and R^(xc) are each independently hydrogen or C₁-C₆alkyl.

In certain embodiments, R^(x1), G¹, R³, and R⁴, are selected from (i)wherein R^(x1) is C₂-C₆ alkynyl substituted with one substituentselected from the group consisting of —NR^(xa)R^(xc) and —OR^(xc) group.In some such embodiments, R^(xa) and R^(xc) are each independentlyhydrogen or C₁-C₆ alkyl.

In certain embodiments, R^(x1), G¹, R³, and R⁴, are selected from (i)wherein R^(x1) is -G^(x1)-G^(x2), C₂-C₆ alkynyl substituted with one—OR^(xc) group, or C₂-C₆ alkenyl substituted with one —C(O)NR^(xa)R^(xc)group. In some such embodiments, G^(x1) is optionally substituted C₅-C₆heteroaryl. In some such embodiments, G^(x1) is pyrazolyl,1,2,4-oxadiazolyl, or pyridinyl; each of which is optionallysubstituted. In some such embodiments, G^(x2) is phenyl, C₅-C₆heteroaryl, C₄-C₆ heterocycle, or C₃-C₆ cycloalkyl; each of which isoptionally substituted. In some such embodiments, G^(x2) is phenyl,thiazolyl, pyridinyl, pyrazinyl, cyclopropyl, cyclohexyl, piperidinyl,tetrahydropyranyl, or morpholinyl; each of which is optionallysubstituted. In some such embodiments, R^(xa) and R^(xc) are eachindependently hydrogen or C₁-C₆ alkyl.

In certain embodiments, R^(x1), G¹, R³, and R⁴, are selected from (i)wherein G¹ is phenyl, C₃-C₆ cycloalkyl, or C₄-C₆ heterocycle, each ofwhich is optionally substituted with 1, 2, 3, 4, or 5 R^(v) groups. Insome such embodiments, each R is independently C₁-C₆ alkyl, halogen,C₁-C₆ haloalkyl, —CN, —OR^(h), or NR^(j)R^(k).

In certain embodiments, R^(x1), G¹, R³, and R⁴, are selected from (i)wherein G¹ is phenyl or C₃-C₆ cycloalkyl, each of which is optionallysubstituted with 1, 2, 3, 4, or 5 R^(v) groups. In some suchembodiments, each R^(v) is independently C₁-C₃ alkyl, halogen, or C₁-C₃haloalkyl.

In certain embodiments, R^(x1), G¹, R³, and R⁴, are selected from (i)wherein G¹ is phenyl or cyclopropyl, each of which is optionallysubstituted with 1, 2, 3, 4, or 5 R^(v) groups. In some suchembodiments, each R^(v) is independently C₁-C₃ alkyl, halogen, or C₁-C₃haloalkyl. In some such embodiments, each G¹ is optionally substitutedwith 1 or 2 halogens. In some such embodiments, the G¹ group issubstituted. In some such embodiments, the halogen is fluorine.

In certain embodiments, R^(x1), G¹, R³, and R⁴, are selected from (i)wherein G¹ is cyclopropyl which is optionally substituted with 1 or 2halogens. In some such embodiments, the halogen is fluorine.

In certain embodiments, R^(x1), G¹, R³, and R⁴, are selected from (i)wherein G¹ is phenyl substituted with 1 or 2 halogens. In some suchembodiments, the halogen is fluorine.

In certain embodiments, R^(x1), G¹, R³, and R⁴, are selected from (i)wherein G¹ is cyclohexyl which is optionally substituted with 1, 2, 3,4, or 5 R^(v) groups. In some such embodiments, each R^(v) isindependently C₁-C₃ alkyl, halogen, or C₁-C₃ haloalkyl. In some suchembodiments, G¹ is unsubstituted cyclohexyl.

In certain embodiments, R^(x1), G¹, R³, and R⁴, are selected from (i)wherein R³ is R^(1a). In some such embodiments, R³ is R^(1a), and R^(1a)is hydrogen.

In certain embodiments, R^(x1), G¹, R³, and R⁴, are selected from (i)wherein R⁴ is R^(1a) In some such embodiments, R⁴ is R^(1a), and R^(1a)is hydrogen.

In certain embodiments, R^(x1), G¹, R³, and R⁴, are selected from (ii).

In certain embodiments, R^(x1), G¹, R³, and R⁴, are selected from (ii)wherein R^(x1) is hydrogen or —C(O)NR^(bx1)R^(cx1).

In certain embodiments, R^(x1), G¹, R³, and R⁴, are selected from (ii)wherein R^(x1) is hydrogen.

In certain embodiments, R^(x1), G¹, R³, and R⁴, are selected from (ii)wherein R^(x1) is —C(O)NR^(bx1)R^(cx1). In some such embodiments,R^(bx1) and R^(cx1) are each independently hydrogen or C₁-C₆ alkyl.

In certain embodiments, R^(x1), G¹, R³, and R⁴, are selected from (ii)wherein G¹ is phenyl, C₃-C₆ cycloalkyl, or C₄-C₆ heterocycle, whereineach G¹ is substituted with one R^(u) group and is optionally furthersubstituted with 1, 2, or 3 R^(v) groups. In some such embodiments, eachR^(v) is independently C₁-C₃ alkyl, halogen, C₁-C₃ haloalkyl, —CN, or—OR^(h). In some such embodiments, each R^(v) is independently C₁-C₃alkyl, halogen, or C₁-C₃ haloalkyl. In some such embodiments, R ishalogen. In some such embodiments, R is Cl. In some embodiments, R^(v)is C₁-C₃ alkyl.

In certain embodiments, R^(x1), G¹, R³, and R⁴, are selected from (ii)wherein G¹ is phenyl, cyclohexyl, or piperidinyl, wherein each G¹ issubstituted with one R^(u) group and is optionally further substitutedwith 1, 2, or 3 R^(v) groups. In some such embodiments, each R^(V) isindependently C₁-C₃ alkyl, halogen, C₁-C₃ haloalkyl, —CN, or —OR^(h). Insome such embodiments, each R^(v) is independently C₁-C₃ alkyl, halogen,or C₁-C₃ haloalkyl. In some such embodiments, R^(v) is halogen. In somesuch embodiments, R^(v) is Cl. In some embodiments, R^(v) is C₁-C₃alkyl.

In certain embodiments, R^(x1), G¹, R³, and R⁴, are selected from (ii)wherein G¹ is phenyl or C₃-C₆, wherein each G¹ is substituted with oneR^(u) group and is optionally further substituted with 1, 2, or 3 R^(v)groups. In some such embodiments, each R is independently C₁-C₃ alkyl,halogen, C₁-C₃ haloalkyl, —CN, or —OR^(h). In some such embodiments,each R^(v) is independently C₁-C₃ alkyl, halogen, or C₁-C₃ haloalkyl. Insome such embodiments, R is halogen. In some such embodiments, R is Cl.In some embodiments, R is C₁-C₃ alkyl.

R^(u) is as described in the Summary and embodiments herein below.

In certain embodiments, R^(u) is —(C₁-C₆ alkylenyl)-G^(u). In certainembodiments, R^(u) is —(C₁-C₆ alkylenyl)-G^(u), and G^(u) is phenyl,C₅-C₆ heteroaryl, or C₄-C₆ heterocycle, each of which is optionallysubstituted. In certain embodiments, R^(u) is —(C₁-C₆ alkylenyl)-G^(u),and G^(u) is phenyl, thienyl, imidazolyl, pyrazolyl, azetidinyl,pyrrolidinyl, 1,2-thiazolidinyl, piperidinyl, pyridin-1(2H)-yl, ormorpholinyl, each of which is optionally substituted. In certainembodiments, R^(u) is —(C₁-C₆ alkylenyl)-G^(u), and G^(u) is phenyl,thienyl, or morpholinyl, each of which is optionally substituted. Incertain embodiments, R^(u) is —(C₁-C₆ alkylenyl)-G^(u), and G^(u) isoptionally substituted phenyl.

In certain embodiments, R^(u) is —(C₂-C₆ alkynylene)-G^(u). In certainembodiments, R^(u) is —(C₂-C₆ alkynylene)-G^(u), and G^(u) is optionallysubstituted C₄-C₆ heterocycle. In certain embodiments, R^(u) is —(C₂-C₆alkynylene)-G^(u), and G^(u) is optionally substituted morpholinyl.

In certain embodiments, R^(u) is —(C₁-C₆ alkylenyl)-SR^(h).

In certain embodiments, R^(u) is —C(O)—Z¹.

In certain embodiments, R^(u) is —C(O)—Z¹ wherein Z¹ is G^(u), —(C₁-C₆alkylenyl)-G^(u), —(C₁-C₆ alkylenyl)-SR^(h), —(C₁-C₆ alkylenyl)-OR^(h),—(C₁-C₆ alkylenyl)-NR^(j)R^(k), or —(C₁-C₆ alkylenyl)-C₁-C₄ alkoxy-C₁-C₄alkoxy. In certain embodiments, G^(u) is phenyl, naphthyl, C₃-C₆cycloalkyl, or C₄-C₆ heterocycle, each of which is optionallysubstituted.

In certain embodiments, R^(u) is —C(O)—NZ¹Z².

In certain embodiments, R^(u) is —C(O)—NZ¹Z² wherein Z¹ is G^(u),—(C₁-C₆ alkylenyl)-G^(u), —(C₁-C₆ alkylenyl)-CN, or —(C₁-C₆alkylenyl)-NR^(j)R^(k), and Z² is hydrogen or C₁-C₃ alkyl. In certainembodiments, G^(u) is phenyl, naphthyl, C₃-C₆ cycloalkyl, or C₄-C₆heterocycle, each of which is optionally substituted.

In certain embodiments, R^(u) is —S(O)₂—Z¹.

In certain embodiments, R^(u) is —S(O)₂—Z¹ wherein Z¹ is G^(u), —(C₁-C₆alkylenyl)-G^(u), or —(C₁-C₆ alkenylene)-G^(u). In certain embodiments,G^(u) is phenyl, naphthyl, C₃-C₆ cycloalkyl, C₅-C₆ heteroaryl, or C₄-C₆heterocycle, each of which is optionally substituted.

In certain embodiments, R^(u) is —N(Z²)Z¹.

In certain embodiments, R^(u) is —N(Z²)Z¹ wherein Z¹ is —(C₁-C₆alkylenyl)-G^(u), —(C₁-C₆ alkylenyl)-SR^(h), or —(C₁-C₆alkylenyl)-OR^(h), and Z² is hydrogen or C₁-C₃ alkyl. In certainembodiments, G^(u) is phenyl, naphthyl, C₃-C₆ cycloalkyl, C₅-C₆heteroaryl, or C₄-C₆ heterocycle, each of which is optionallysubstituted.

In certain embodiments, R^(u) is —N(Z²)Z¹ wherein Z¹ is —(C₁-C₆alkylenyl)-G^(u), and Z² is hydrogen or C₁-C₃ alkyl. In some suchembodiments, G^(u) is phenyl or naphthyl, each of which is optionallysubstituted.

In certain embodiments, R^(u) is —N(Z²)S(O)₂—Z¹.

In certain embodiments, R^(u) is —N(Z²)S(O)₂—Z¹, wherein Z¹ is G^(u) or—(C₁-C₆ alkylenyl)-G^(u), and Z² is hydrogen or C₁-C₃ alkyl. In certainembodiments, G^(u) is phenyl, naphthyl, C₃-C₆ cycloalkyl, C₅-C₆heteroaryl, or C₄-C₆ heterocycle, each of which is optionallysubstituted.

In certain embodiments, R^(u) is —N(Z²)S(O)₂—Z¹, wherein Z¹ is G^(u),and Z² is hydrogen. In certain embodiments, G^(u) is optionallysubstituted C₃-C₆ cycloalkyl. In certain embodiments, G^(u) isoptionally substituted cyclopropyl. In certain embodiments, the optionalsubstituents are C₁-C₃ alkyl, halogen, and C₁-C₃ haloalkyl.

In certain embodiments, R^(u) is —(C₁-C₆ alkylenyl)-G^(u), —N(Z²)Z¹, or—N(Z²)S(O)₂—Z¹.

In certain embodiments, R^(u) is —(C₁-C₆ alkylenyl)-G^(u) and G^(u) isphenyl, C₅-C₆ heteroaryl, or C₄-C₆ heterocycle, each of which isoptionally substituted; or R^(u) is —N(Z²)S(O)₂—Z¹, wherein Z¹ is G^(u),and Z² is hydrogen; or R^(u) is —N(Z²)Z¹ wherein Z¹ is —(C₁-C₆alkylenyl)-G^(u), and Z² is hydrogen or C₁-C₃ alkyl.

In certain embodiments, R^(u) is —(C₁-C₆ alkylenyl)-G_(u) and G^(u) isoptionally substituted phenyl; or R^(u) is —N(Z²)S(O)₂—Z¹, wherein Z¹ isG^(u) and G^(u) is optionally substituted C₃-C₆ cycloalkyl, and Z² ishydrogen; or R^(u) is —N(Z²)Z¹ wherein Z¹ is —(C₁-C₆ alkylenyl)-Gwherein G^(u) is phenyl or naphthyl, each of which is optionallysubstituted, and Z² is hydrogen or C₁-C₃ alkyl.

In certain embodiments, R^(x1), G¹, R³, and R⁴, are selected from (ii)wherein R³ is R^(1a). In some such embodiments, R³ is R^(1a), and R^(1a)is hydrogen.

In certain embodiments, R^(x1), G¹, R³, and R⁴, are selected from (ii)wherein R⁴ is R^(1a). In some such embodiments, R⁴ is R^(1a), and R^(1a)is hydrogen.

In certain embodiments, R^(x1), G¹, R³, and R⁴, are selected from (iii).

In certain embodiments, R^(x1), G¹, R³, and R⁴, are selected from (iii)wherein R^(x1) is hydrogen or —C(O)NR^(bx1)R^(cx1).

In certain embodiments, R^(x1), G¹, R³, and R⁴, are selected from (iii)wherein R^(x1) is hydrogen.

In certain embodiments, R^(x1), G¹, R³, and R⁴, are selected from (iii)wherein R^(x1) is —C(O)NR^(bx1)R^(cx1). In some such embodiments,R^(bx1) and R^(cx1) are each independently hydrogen or C₁-C₆ alkyl.

In certain embodiments, R^(x1), G¹, R³, and R⁴, are selected from (iii)wherein G¹ is phenyl, C₃-C₆ cycloalkyl, or C₄-C₆ heterocycle, each ofwhich is optionally substituted with 1, 2, 3, 4, or 5 R^(v) groups. Insome such embodiments, each R is independently C₁-C₆ alkyl, halogen,C₁-C₆ haloalkyl, —CN, —OR^(h), or NR^(j)R^(k).

In certain embodiments, R^(x1), G¹, R³, and R⁴, are selected from (iii)wherein G¹ is phenyl or C₃-C₆ cycloalkyl, each of which is optionallysubstituted with 1, 2, 3, 4, or 5 R^(v) groups. In some suchembodiments, each R^(v) is independently C₁-C₃ alkyl, halogen, or C₁-C₃haloalkyl.

In certain embodiments, R^(x1), G¹, R³, and R⁴, are selected from (iii)wherein G¹ is phenyl or cyclopropyl, each of which is optionallysubstituted with 1, 2, 3, 4, or 5 R^(v) groups. In some suchembodiments, each R is independently C₁-C₃ alkyl, halogen, or C₁-C₃haloalkyl. In some such embodiments, each G¹ is optionally substitutedwith 1 or 2 halogens. In some such embodiments, the G¹ group issubstituted. In some such embodiments, the halogen is fluorine.

In certain embodiments, R^(x1), G¹, R³, and R⁴, are selected from (iii)wherein G¹ is cyclopropyl which is optionally substituted with 1 or 2halogens. In some such embodiments, the halogen is fluorine.

In certain embodiments, R^(x1), G¹, R³, and R⁴, are selected from (iii)wherein G¹ is phenyl substituted with 1 or 2 halogens. In some suchembodiments, the halogen is fluorine.

In certain embodiments, R^(x1), G¹, R³, and R⁴, are selected from (iii)wherein R³ is —C(O)OH, —C(O)NR^(3a)R^(3b), G^(3a), —(C₁-C₆alkylenyl)-OR^(3a), —(C₁-C₆ alkylenyl)-NR^(3a)R^(3b), —(C₁-C₆alkylenyl)-G^(3a), or —(C₁-C₆ alkylenyl)-G^(3a)-G^(3b). In certainembodiments, G^(3a) and G^(3b) are each independently phenyl, C₃-C₆cycloalkyl, C₅-C₆ heteroaryl, or C₄-C₆ heterocycle, each of which isoptionally substituted.

In certain embodiments, R^(x1), G¹, R³, and R⁴, are selected from (iii)wherein R³ is —C(O)OH, —C(O)NR^(3a)R^(3b), or —(C₁-C₆ alkylenyl)-G^(3a).In some such embodiments, G^(3a) is optionally substituted C₄-C₆heterocycle. In some such embodiments, G^(3a) is piperidinyl ormorpholinyl, each of which is optionally substituted.

In certain embodiments, R^(x1), G¹, R³, and R⁴, are selected from (iii)wherein R³ is —C(O)OH.

In certain embodiments, R^(x1), G¹, R³, and R⁴, are selected from (iii)wherein R³ is —C(O)NR^(3a)R^(3b).

In certain embodiments, R^(x1), G¹, R³, and R⁴, are selected from (iii)wherein R³ is —C(O)NR^(3a)R^(3b), wherein R^(3a) is hydrogen, C₁-C₃alkyl, —(C₁-C₆ alkylenyl)-G^(3a), or C₁-C₆ alkyl substituted with onesubstituent selected from the group consisting of —C(O)NR^(j)R^(k) and—C(O)OR^(h), and R^(3b) is hydrogen, C₁-C₃ alkyl, G^(3a), or —(C₁-C₆alkylenyl)-G^(3a). In some such embodiments, G^(3a) is phenyl, C₃-C₆cycloalkyl, C₅-C₆ heteroaryl, or C₄-C₆ heterocycle, each of which isoptionally substituted. In some such embodiments, G^(3a) is phenyl,C₃-C₆ cycloalkyl, or C₄-C₆ heterocycle, each of which is optionallysubstituted. In some such embodiments, G^(3a) is phenyl, pyridinyl,thiomorpholinyl, morpholinyl, piperidinyl, tetrahydropyranyl orcyclopentyl, each of which is optionally substituted.

In certain embodiments, R^(x1), G¹, R³, and R⁴, are selected from (iii)wherein R³ is —C(O)NR^(3a)R^(3b), wherein R^(3a) is hydrogen or C₁-C₃alkyl, and R^(3b) is hydrogen, C₁-C₃ alkyl, or G^(3a). In some suchembodiments, G^(3a) is phenyl, C₃-C₆ cycloalkyl, C₅-C₆ heteroaryl, orC₄-C₆ heterocycle, each of which is optionally substituted. In some suchembodiments, G^(3a) is C₃-C₆ cycloalkyl or C₄-C₆ heterocycle, each ofwhich is optionally substituted. In some such embodiments, G^(3a) isoptionally substituted tetrahydropyranyl or optionally substitutedcyclopentyl.

In certain embodiments, R^(x1), G¹, R³, and R⁴, are selected from (iii)wherein R³ is G^(3a). In some such embodiments, G^(3a) is phenyl, C₃-C₆cycloalkyl, C₅-C₆ heteroaryl, or C₄-C₆ heterocycle, each of which isoptionally substituted. In some such embodiments, G^(3a) is optionallysubstituted C₅-C₆ heteroaryl. In some such embodiments, G^(3a) isoptionally substituted pyrazolyl. In some such embodiments, G^(3a) isoptionally substituted with 1 or 2 substituents independently selectedfrom the group consisting of C₁-C₃ alkyl, C₁-C₃ haloalkyl, or halogen.

In certain embodiments, R^(x1), G¹, R³, and R⁴, are selected from (iii)wherein R³ is —(C₁-C₆ alkylenyl)-OR^(3a). In some such embodiments,R^(3a) is hydrogen, C₁-C₆ alkyl, or C₁-C₆ haloalkyl. In some suchembodiments, R^(3a) is hydrogen or C₁-C₃ alkyl. In some suchembodiments, R^(3a) is hydrogen.

In certain embodiments, R^(x1), G¹, R³, and R⁴, are selected from (iii)wherein R³ is —(C₁-C₆ alkylenyl)-NR^(3a)R^(3b). In some suchembodiments, R^(3a) is hydrogen or C₁-C₃ alkyl, and R^(3b) is hydrogen,C₁-C₃ alkyl, G^(3a), or C₂-C₆ alkyl substituted with one OR^(h) group.In some such embodiments, G^(3a) is phenyl, C₃-C₆ cycloalkyl, C₅-C₆heteroaryl, or C₄-C₆ heterocycle, each of which is optionallysubstituted. In some such embodiments, G^(3a) is optionally substitutedC₃-C₆ cycloalkyl. In some such embodiments, G^(3a) is optionallysubstituted cyclopentyl.

In certain embodiments, R^(x1), G¹, R³, and R⁴, are selected from (iii)wherein R³ is —(C₁-C₆ alkylenyl)-G^(3a). In some such embodiments,G^(3a) is phenyl, C₃-C₆ cycloalkyl, C₅-C₆ heteroaryl, or C₄-C₆heterocycle, each of which is optionally substituted. In some suchembodiments, G^(3a) is optionally substituted C₄-C₆ heterocycle. In somesuch embodiments, G^(3a) is morpholinyl, piperidinyl, or piperazinyl,each of which is optionally substituted.

In certain embodiments, R^(x1), G¹, R³, and R⁴, are selected from (iii)wherein R³ is —(C₁-C₆ alkylenyl)-G^(3a)-G^(3b). In some suchembodiments, G^(3a) and G^(3b) are each independently phenyl, C₃-C₆cycloalkyl, C₅-C₆ heteroaryl, or C₄-C₆ heterocycle, each of which isoptionally substituted. In some such embodiments, G^(3a) is optionallysubstituted C₄-C₆ heterocycle. In some such embodiments, G^(3a) isoptionally substituted pyrrolidinyl.

In certain embodiments, R^(x1), G¹, R³, and R⁴, are selected from (iii)wherein R⁴ is R^(1a) In some such embodiments, R⁴ is R^(1a), and R^(1a)is hydrogen.

In certain embodiments, R^(x1), G¹, R³, and R⁴, are selected from (iv).

In certain embodiments, R^(x1), G¹, R³, and R⁴, are selected from (iv)wherein R^(x1) is hydrogen.

In certain embodiments, R^(x1), G¹, R³, and R⁴, are selected from (iv)wherein G¹ is phenyl, C₃-C₆ cycloalkyl, or C₄-C₆ heterocycle, each ofwhich is optionally substituted with 1, 2, 3, 4, or 5 R^(v) groups. Insome such embodiments, each R is independently C₁-C₆ alkyl, halogen,C₁-C₆ haloalkyl, —CN, —OR^(h), or NR^(j)R^(k).

In certain embodiments, R^(x1), G¹, R³, and R⁴, are selected from (iv)wherein G¹ is phenyl or C₃-C₆ cycloalkyl, each of which is optionallysubstituted with 1, 2, 3, 4, or 5 R^(v) groups. In some suchembodiments, each R^(v) is independently C₁-C₃ alkyl, halogen, or C₁-C₃haloalkyl.

In certain embodiments, R^(x1), G¹, R³, and R⁴, are selected from (iv)wherein G¹ is phenyl or cyclopropyl, each of which is optionallysubstituted with 1, 2, 3, 4, or 5 R^(v) groups. In some suchembodiments, each R^(v) is independently C₁-C₃ alkyl, halogen, or C₁-C₃haloalkyl. In some such embodiments, each G¹ is optionally substitutedwith 1 or 2 halogens. In some such embodiments, the G¹ group issubstituted. In some such embodiments, the halogen is fluorine.

In certain embodiments, R^(x1), G¹, R³, and R⁴, are selected from (iv)wherein G¹ is cyclopropyl which is optionally substituted with 1 or 2halogens. In some such embodiments, the halogen is fluorine.

In certain embodiments, R^(x1), G¹, R³, and R⁴, are selected from (iv)wherein G¹ is phenyl substituted with 1 or 2 halogens. In some suchembodiments, the halogen is fluorine.

In certain embodiments, R^(x1), G¹, R³, and R⁴, are selected from (iv)wherein R³ is R^(1a). In some such embodiments, R³ is R^(1a), and R^(1a)is hydrogen.

In certain embodiments, R^(x1), G¹, R³, and R⁴, are selected from (iv)wherein R⁴ is G⁴. In some such embodiments, G⁴ is optionally substitutedC₃-C₆ cycloalkyl. In some such embodiments, G⁴ is optionally substitutedcyclopropyl. In some such embodiments, G⁴ is unsubstituted cyclopropyl.

Various embodiments of substituents R^(x), R^(y), R^(x1), L¹, G¹, A¹,A², A³, and A⁴ have been discussed above. These substituents embodimentscan be combined to form various embodiments of compounds of formula (I).All embodiments of compounds of formula (I), formed by combining thesubstituent embodiments discussed above are within the scope ofApplicant's invention, and some illustrative embodiments of thecompounds of formula (I) are provided below.

In one embodiment, the invention is directed to compounds of formula(I), wherein R^(x) is hydrogen, and R^(y) is C₁-C₃ alkyl.

In one embodiment, the invention is directed to compounds of formula(I), wherein R^(x) is hydrogen, R^(y) is C₁-C₃ alkyl, A¹ is CR¹, A² isCR², A³ is CR³; and A⁴ is CR⁴.

In one embodiment, the invention is directed to compounds of formula(I), wherein R^(x) is hydrogen, R^(y) is C₁-C₃ alkyl, and one of A¹, A²,A³, and A⁴ is N.

In one embodiment, the invention is directed to compounds of formula(I), wherein R^(x) is hydrogen, R^(y) is C₁-C₃ alkyl, R² is hydrogen,—S(O)₂R^(2a), or —N(R^(2b))S(O)₂R^(2a); R^(2a) is C₁-C₃ alkyl; andR^(2b) is hydrogen.

In one embodiment, the invention is directed to compounds of formula(I), wherein R^(x) is hydrogen, R^(y) is methyl, A¹ is CR¹, A² is CR²,A³ is CR³; and A⁴ is CR⁴, R¹ is hydrogen, and R^(x1), G¹, R³, and R⁴,are selected from (i).

In one embodiment, the invention is directed to compounds of formula(I), wherein R^(x) is hydrogen, R^(y) is methyl, A¹ is CR¹, A² is CR²,A³ is CR³; and A⁴ is CR⁴, R¹ is hydrogen, R^(x1), G¹, R³, and R⁴, areselected from (i) wherein R³ is R^(1a); R⁴ is R^(1a); and G¹ is phenyl,C₃-C₆ cycloalkyl, or C₄-C₆ heterocycle, each of which is optionallysubstituted with 1, 2, 3, 4, or 5 R^(v) groups.

In one embodiment, the invention is directed to compounds of formula(I), wherein R^(x) is hydrogen, R^(y) is methyl, A¹ is CR¹, A² is CR²,A³ is CR³; and A⁴ is CR⁴, R¹ is hydrogen, R^(x1), G¹, R³, and R⁴, areselected from (i) wherein R³ is R^(1a); R⁴ is R^(1a); R^(1a) ishydrogen; and G¹ is phenyl or C₃-C₆ cycloalkyl, each of which isoptionally substituted with 1, 2, 3, 4, or 5 R^(v) groups.

In one embodiment, the invention is directed to compounds of formula(I), wherein R^(x) is hydrogen, R^(y) is methyl, A¹ is CR¹, A² is CR²,A³ is CR³; and A⁴ is CR⁴, R¹ is hydrogen, R^(x1), G¹, R³, and R⁴, areselected from (i) wherein R³ is R^(1a); R⁴ is R^(1a); R^(1a) ishydrogen; G¹ is phenyl or C₃-C₆ cycloalkyl, each of which is optionallysubstituted with 1, 2, 3, 4, or 5 R^(v) groups; and R^(x1) is-G^(x1)-G^(x2), —(C₁-C₆ alkylenyl)-G^(x1)-G^(x2),—C(O)N(R^(xa))(R^(xb)), C₂-C₆ alkenyl, or C₂-C₆ alkynyl; wherein theC₂-C₆ alkenyl and C₂-C₆ alkynyl are each independently substituted withone substituent selected from the group consisting of —CN, —OR^(xc),—SR^(xc), —S(O)R^(xc), —S(O)₂R^(xc), —NR^(xa)R^(xc), —C(O)R^(xc),—C(O)OR^(xc), —C(O)NR^(xa)R^(xc), —S(O)₂NR^(xa)R^(xc), and G^(x1).

In one embodiment, the invention is directed to compounds of formula(I), wherein R^(x) is hydrogen, R^(y) is methyl, A¹ is CR¹, A² is CR²,A³ is CR³; and A⁴ is CR⁴, R¹ is hydrogen, R^(x1), G¹, R³, and R⁴, areselected from (i) wherein R³ is R^(1a); R⁴ is R^(1a); R^(1a) ishydrogen; G¹ is phenyl or C₃-C₆ cycloalkyl, each of which is optionallysubstituted with 1, 2, 3, 4, or 5 R^(v) groups; R^(x1) is-G^(x1)-G^(x2), —(C₁-C₆ alkylenyl)-G^(x1)-G^(x2),—C(O)N(R^(xa))(R^(xb)), C₂-C₆ alkenyl, or C₂-C₆ alkynyl; wherein theC₂-C₆ alkenyl and C₂-C₆ alkynyl are each independently substituted withone substituent selected from the group consisting of —CN, —OR^(xc),—SR^(xc), —S(O)R^(xc), —S(O)₂R^(xc), —NR^(xa)R^(xc), —C(O)R^(xc),—C(O)OR^(xc), —C(O)NR^(xa)R^(xc), —S(O)₂NR^(xa)R^(xc), and G^(x1); andR² is hydrogen, —S(O)₂R^(2a), or —N(R^(2b))S(O)₂R^(2a).

In one embodiment, the invention is directed to compounds of formula(I), wherein R^(x) is hydrogen, R^(y) is methyl, A¹ is CR¹, A² is CR²,A³ is CR³; and A⁴ is CR⁴, R¹ is hydrogen, R^(x1), G¹, R³, and R⁴, areselected from (i) wherein R³ is R^(1a); R⁴ is R^(1a); R^(1a) ishydrogen; G¹ is phenyl or C₃-C₆ cycloalkyl, each of which is optionallysubstituted with 1, 2, 3, 4, or 5 R groups; R^(x1) is -G^(x1)-G^(x2),C₂-C₆ alkynyl substituted with one —OR^(xc) group, or C₂-C₆ alkenylsubstituted with one —C(O)NR^(xa)R^(xc) group; and R² is hydrogen,—S(O)₂R^(2a), or —N(R^(2b))S(O)₂R^(2a). In some such embodiments, R^(xa)and R^(xb) are each independently hydrogen or C₁-C₆ alkyl.

In one embodiment, the invention is directed to compounds of formula(I), wherein R^(x) is hydrogen, R^(y) is methyl, A¹ is CR¹, A² is CR²,A³ is CR³; and A⁴ is CR⁴, R¹ is hydrogen, and R^(x1), G¹, R³, and R⁴,are selected from (ii).

In one embodiment, the invention is directed to compounds of formula(I), wherein R^(x) is hydrogen, R^(y) is methyl, A¹ is CR¹, A² is CR²,A³ is CR³; and A⁴ is CR⁴, R¹ is hydrogen, R^(x1), G¹, R³, and R⁴, areselected from (ii) wherein R^(x1) is hydrogen or—C(O)N(R^(bx1))(R^(cx1)); R³ is R^(1a); R⁴ is R^(1a); and G¹ is phenyl,C₃-C₆ cycloalkyl, or C₄-C₆ heterocycle, wherein each G¹ is substitutedwith one R^(u) group and is optionally further substituted with 1, 2, or3 R^(v) groups.

In one embodiment, the invention is directed to compounds of formula(I), wherein R^(x) is hydrogen, R^(y) is methyl, A¹ is CR¹, A² is CR²,A³ is CR³; and A⁴ is CR⁴, R¹ is hydrogen, R^(x1), G¹, R³, and R⁴, areselected from (ii) wherein R^(x1) is hydrogen or—C(O)N(R^(bx1))(R^(cx1)); R³ is R^(1a); R⁴ is R^(1a); R^(1a) ishydrogen; G¹ is phenyl, C₃-C₆ cycloalkyl, or C₄-C₆ heterocycle, whereineach G¹ is substituted with one R^(u) group and is optionally furthersubstituted with 1, 2, or 3 R^(v) groups; and R² is hydrogen,—S(O)₂R^(2a), or —N(R^(2b))S(O)₂R^(2a).

In one embodiment, the invention is directed to compounds of formula(I), wherein R^(x) is hydrogen, R^(y) is methyl, A¹ is CR¹, A² is CR²,A³ is CR³; and A⁴ is CR⁴, R¹ is hydrogen, R^(x1), G¹, R³, and R⁴, areselected from (ii) wherein R^(x1) is hydrogen or—C(O)N(R^(bx1))(R^(cx1)); R³ is R^(1a); R⁴ is R^(1a); R^(1a) ishydrogen; G¹ is phenyl or C₃-C₆ cycloalkyl, wherein each G¹ issubstituted with one R^(u) group and is optionally further substitutedwith 1, 2, or 3 R^(v) groups; R² is hydrogen, —S(O)₂R^(2a), or—N(R^(2b))S(O)₂R^(2a); and R^(u) is —(C₁-C₆ alkylenyl)-G^(u), —N(Z²)Z¹,or —N(Z²)S(O)₂—Z¹.

In one embodiment, the invention is directed to compounds of formula(I), wherein R^(x) is hydrogen, R^(y) is methyl, A¹ is CR¹, A² is CR²,A³ is CR³; and A⁴ is CR⁴, R¹ is hydrogen, and R^(x1), G¹, R³, and R⁴,are selected from (iii).

In one embodiment, the invention is directed to compounds of formula(I), wherein R^(x) is hydrogen, R^(y) is methyl, A¹ is CR¹, A² is CR²,A³ is CR³; and A⁴ is CR⁴, R¹ is hydrogen, R^(x1), G¹, R³, and R⁴, areselected from (iii) wherein R^(x1) is hydrogen or —C(O)NR^(bx1)R^(cx1);R⁴ is R^(1a); and G¹ is phenyl, C₃-C₆ cycloalkyl, or C₄-C₆ heterocycle,each of which is optionally substituted with 1, 2, 3, 4, or 5 R^(v)groups.

In one embodiment, the invention is directed to compounds of formula(I), wherein R^(x) is hydrogen, R^(y) is methyl, A¹ is CR¹, A² is CR²,A³ is CR³; and A⁴ is CR⁴, R¹ is hydrogen, R^(x1), G¹, R³, and R⁴, areselected from (iii) wherein R^(x1) is hydrogen or —C(O)NR^(bx1)R^(cx1);R⁴ is R^(1a); R^(1a) is hydrogen; and G¹ is phenyl or C₃-C₆ cycloalkyl,each of which is optionally substituted with 1, 2, 3, 4, or 5 R^(v)groups.

In one embodiment, the invention is directed to compounds of formula(I), wherein R^(x) is hydrogen, R^(y) is methyl, A¹ is CR¹, A² is CR²,A³ is CR³; and A⁴ is CR⁴, R¹ is hydrogen, R^(x1), G¹, R³, and R⁴, areselected from (iii) wherein R^(x1) is hydrogen; R⁴ is R^(1a); R^(1a) ishydrogen or —C(O)NR^(bx1)R^(cx1); G¹ is phenyl or C₃-C₆ cycloalkyl, eachof which is optionally substituted with 1, 2, 3, 4, or 5 R^(v) groups;and R³ is —C(O)OH, —C(O)NR^(3a)R^(3b), G^(3a), —(C₁-C₆alkylenyl)-OR^(3a), —(C₁-C₆ alkylenyl)-NR^(3a)R^(3b), —(C₁-C₆alkylenyl)-G^(3a), or —(C₁-C₆ alkylenyl)-G^(3a)-G^(3b).

In one embodiment, the invention is directed to compounds of formula(I), wherein R^(x) is hydrogen, R^(y) is methyl, A¹ is CR¹, A² is CR²,A³ is CR³; and A⁴ is CR⁴, R¹ is hydrogen, R^(x1), G¹, R³, and R⁴, areselected from (iii) wherein R^(x1) is hydrogen or —C(O)NR^(bx1)R^(cx1);R⁴ is R^(1a); R^(1a) is hydrogen; G¹ is phenyl or C₃-C₆ cycloalkyl, eachof which is optionally substituted with 1, 2, 3, 4, or 5 R^(v) groups;R³ is —C(O)OH, —C(O)NR^(3a)R^(3b), G^(3a), —(C₁-C₆ alkylenyl)-OR^(3a),—(C₁-C₆ alkylenyl)-NR^(3a)R^(3b), —(C₁-C₆ alkylenyl)-G^(3a), or —(C₁-C₆alkylenyl)-G^(3a)-G^(3b); and R² is hydrogen, —S(O)₂R^(2a), or—N(R^(2b))S(O)₂R^(2a).

In one embodiment, the invention is directed to compounds of formula(I), wherein R^(x) is hydrogen, R^(y) is methyl, A¹ is CR¹, A² is CR²,A³ is CR³; and A⁴ is CR⁴, R¹ is hydrogen, R^(x1), G¹, R³, and R⁴, areselected from (iii) wherein R^(x1) is hydrogen or —C(O)NR^(bx1)R^(cx1);R⁴ is R^(1a); R^(1a) is hydrogen; G¹ is phenyl which is optionallysubstituted with 1, 2, 3, 4, or 5 R^(v) groups; R³ is —C(O)OH,—C(O)NR^(3a)R^(3b), or —(C₁-C₆ alkylenyl)-G^(3a); and R² is hydrogen,—S(O)₂R^(2a), or —N(R^(2b))S(O)₂R^(2a). In some such embodiments, G^(3a)is optionally substituted C₄-C₆ heterocycle. In some such embodiments,G^(3a) is piperidinyl or morpholinyl, each of which is optionallysubstituted.

In one embodiment, the invention is directed to compounds of formula(I), wherein R^(x) is hydrogen, R^(y) is methyl, A¹ is CR¹, A² is CR²,A³ is CR³; and A⁴ is CR⁴, R¹ is hydrogen, and R^(x1), G¹, R³, and R⁴,are selected from (iv).

In one embodiment, the invention is directed to compounds of formula(I), wherein R^(x) is hydrogen, R^(y) is methyl, A¹ is CR¹, A² is CR²,A³ is CR³; and A⁴ is CR⁴, R¹ is hydrogen, and R^(x1), G¹, R³, and R⁴,are selected from (iv) wherein R^(x1) is hydrogen; R³ is R^(1a); and G¹is phenyl, C₃-C₆ cycloalkyl, or C₄-C₆ heterocycle, each of which isoptionally substituted with 1, 2, 3, 4, or 5 R^(v) groups.

In one embodiment, the invention is directed to compounds of formula(I), wherein R^(x) is hydrogen, R^(y) is methyl, A¹ is CR¹, A² is CR²,A³ is CR³; and A⁴ is CR⁴, R¹ is hydrogen, and R^(x1), G¹, R³, and R⁴,are selected from (iv) wherein R^(x1) is hydrogen; R³ is R^(1a); R^(1a)is hydrogen; and G¹ is phenyl or C₃-C₆ cycloalkyl, each of which isoptionally substituted with 1, 2, 3, 4, or 5 R^(v) groups.

In one embodiment, the invention is directed to compounds of formula(I), wherein R^(x) is hydrogen, R^(y) is methyl, A¹ is CR¹, A² is CR²,A³ is CR³; and A⁴ is CR⁴, R¹ is hydrogen, and R^(x1), G¹, R³, and R⁴,are selected from (iv) wherein R^(x1) is hydrogen; R³ is R^(1a); R^(1a)is hydrogen; G¹ is phenyl or C₃-C₆ cycloalkyl, each of which isoptionally substituted with 1, 2, 3, 4, or 5 R^(v) groups, and R⁴ isoptionally substituted C₃-C₆ cycloalkyl.

In one embodiment, the invention is directed to compounds of formula(I), wherein R^(x) is hydrogen, R^(y) is methyl, A¹ is CR¹, A² is CR²,A³ is CR³; and A⁴ is CR⁴, R¹ is hydrogen, and R^(x1), G¹, R³, and R⁴,are selected from (iv) wherein R^(x1) is hydrogen; R³ is R^(1a); R^(1a)is hydrogen; G¹ is phenyl or C₃-C₆ cycloalkyl, each of which isoptionally substituted with 1, 2, 3, 4, or 5 R^(v) groups, R⁴ isoptionally substituted cyclopropyl, and R² is hydrogen, —S(O)₂R^(2a), or—N(R^(2b))S(O)₂R^(2a).

Compounds of formula (I) may contain one or more asymmetricallysubstituted atoms. Compounds of formula (I) may also exist as individualstereoisomers (including enantiomers and diastereomers) and mixturesthereof. Individual stereoisomers of compounds of formula (I) may beprepared synthetically from commercially available starting materialsthat contain asymmetric or chiral centers or by preparation of racemicmixtures followed by resolution of the individual stereoisomer usingmethods that are known to those of ordinary skill in the art. Examplesof resolution are, for example, (i) attachment of a mixture ofenantiomers to a chiral auxiliary, separation of the resulting mixtureof diastereomers by recrystallization or chromatography, followed byliberation of the optically pure product; or (ii) separation of themixture of enantiomers or diastereomers on chiral chromatographiccolumns.

Compounds of formula (I) may also include the various geometric isomersand mixtures thereof resulting from the disposition of substituentsaround a carbon-carbon double bond, a carbon-nitrogen double bond, acycloalkyl group, or a heterocycle group. Substituents around acarbon-carbon double bond or a carbon-nitrogen double bond aredesignated as being of Z or E configuration and substituents around acycloalkyl or heterocycle are designated as being of cis or transconfiguration.

Within the present invention it is to be understood that compoundsdisclosed herein may exhibit the phenomenon of tautomerism and alltautomeric isomers are included in the scope of the invention.

Thus, the formula drawings within this specification can represent onlyone of the possible tautomeric, geometric, or stereoisomeric forms. Itis to be understood that the invention encompasses any tautomeric,geometric, or stereoisomeric form, and mixtures thereof, and is not tobe limited merely to any one tautomeric, geometric, or stereoisomericform utilized within the formula drawings.

Exemplary compounds of formula (I) include, but are not limited to:

-   4-[2-(cyclopropylmethoxy)-4-(3-methyl-1H-pyrazol-5-yl)phenyl]-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one;-   N-[4-(2,4-difluorophenoxy)-2-[(dimethylamino)methyl]-5-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)phenyl]ethanesulfonamide;-   N-[4-(2,4-difluorophenoxy)-5-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-2-(piperidin-1-ylmethyl)phenyl]ethanesulfonamide;-   N-[4-(2,4-difluorophenoxy)-5-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-2-(morpholin-4-ylmethyl)phenyl]ethanesulfonamide;-   N-{4-(2,4-difluorophenoxy)-5-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-2-[(4-methylpiperazin-1-yl)methyl]phenyl}ethanesulfonamide;-   N-[4-(2,4-difluorophenoxy)-2-(hydroxymethyl)-5-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)phenyl]ethanesulfonamide;-   N-{2-[(cyclopentylamino)methyl]-4-(2,4-difluorophenoxy)-5-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)phenyl}ethanesulfonamide;-   5-(2,4-difluorophenoxy)-2-[(ethylsulfonyl)amino]-4-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)benzamide;-   N-cyclopentyl-5-(2,4-difluorophenoxy)-2-[(ethylsulfonyl)amino]-4-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)benzamide;-   5-(2,4-difluorophenoxy)-2-[(ethylsulfonyl)amino]-N,N-dimethyl-4-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)benzamide;-   5-(2,4-difluorophenoxy)-2-[(ethylsulfonyl)amino]-4-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)benzoic    acid;-   5-(2,4-difluorophenoxy)-2-[(ethylsulfonyl)amino]-4-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-N-(tetrahydro-2H-pyran-4-yl)benzamide;-   N-[4-(2,4-difluorophenoxy)-2-{[(2-hydroxyethyl)amino]methyl}-5-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)phenyl]ethanesulfonamide;-   N-{4-(2,4-difluorophenoxy)-5-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-2-[(2-phenylpyrrolidin-1-yl)methyl]phenyl}ethanesulfonamide;-   N-[3-cyclopropyl-4-(2,4-difluorophenoxy)-5-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)phenyl]ethanesulfonamide;-   4-{2-[(2,2-difluorocyclopropyl)methoxy]-5-(ethylsulfonyl)phenyl}-6-methyl-2-{[4-(pyridin-4-yl)piperazin-1-yl]methyl}-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one;-   4-{2-[(2,2-difluorocyclopropyl)methoxy]-5-(ethylsulfonyl)phenyl}-6-methyl-2-{[4-(1,3-thiazol-2-yl)piperazin-1-yl]methyl}-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one;-   4-{2-[(2,2-difluorocyclopropyl)methoxy]-5-(ethylsulfonyl)phenyl}-6-methyl-2-{[4-(pyrazin-2-yl)piperazin-1-yl]methyl}-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one;-   4-{2-[(2,2-difluorocyclopropyl)methoxy]-5-(ethylsulfonyl)phenyl}-6-methyl-2-{[4-(pyrimidin-2-yl)piperazin-1-yl]methyl}-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one;-   4-{2-[(2,2-difluorocyclopropyl)methoxy]-5-(ethylsulfonyl)phenyl}-6-methyl-2-{[4-(pyridin-3-yl)piperazin-1-yl]methyl}-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one;-   N-cyclopropyl-3-[2-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-4-(methylsulfonyl)phenoxy]benzamide;-   6-methyl-4-[2-{3-[(4-methylpiperazin-1-yl)carbonyl]phenoxy}-5-(methylsulfonyl)phenyl]-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one;-   4-{2-[3-({4-[2-(1H-imidazol-1-yl)ethyl]piperazin-1-yl}carbonyl)phenoxy]-5-(methylsulfonyl)phenyl}-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one;-   6-methyl-4-[5-(methylsulfonyl)-2-(3-{[4-(pyrrolidin-1-yl)piperidin-1-yl]carbonyl}phenoxy)phenyl]-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one;    N-cyclohexyl-3-[2-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-4-(methylsulfonyl)phenoxy]benzamide;-   4-[2-(3-{[4-(2-hydroxyethyl)piperazin-1-yl]carbonyl}phenoxy)-5-(methylsulfonyl)phenyl]-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one;-   3-[2-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-4-(methylsulfonyl)phenoxy]-N-[3-(2-oxopyrrolidin-1-yl)propyl]benzamide;-   4-[2-{3-[(4-cyclopentylpiperazin-1-yl)carbonyl]phenoxy}-5-(methylsulfonyl)phenyl]-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one;-   4-{2-[3-({4-[2-(dimethylamino)ethyl]piperazin-1-yl}carbonyl)phenoxy]-5-(methylsulfonyl)phenyl}-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one;-   4-[2-{3-[(4-acetylpiperazin-1-yl)carbonyl]phenoxy}-5-(methylsulfonyl)phenyl]-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one;-   6-methyl-4-[5-(methylsulfonyl)-2-(3-{[4-(trifluoromethyl)piperidin-1-yl]carbonyl}phenoxy)phenyl]-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one;-   N-(cyanomethyl)-N-methyl-3-[2-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-4-(methylsulfonyl)phenoxy]benzamide;-   N-[2-(dimethylamino)ethyl]-3-[2-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-4-(methylsulfonyl)phenoxy]benzamide;-   3-[2-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-4-(methylsulfonyl)phenoxy]-N-[(2R)-tetrahydrofuran-2-ylmethyl]benzamide;-   3-[2-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-4-(methylsulfonyl)phenoxy]-N-[2-(pyrrolidin-1-yl)ethyl]benzamide;-   N-(3,5-difluorobenzyl)-3-[2-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-4-(methylsulfonyl)phenoxy]benzamide;-   N-(2,4-difluorobenzyl)-3-[2-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-4-(methylsulfonyl)phenoxy]benzamide;-   N-{3-[2-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-4-(methylsulfonyl)phenoxy]phenyl}-1-phenylmethanesulfonamide;-   4-methoxy-N-{3-[2-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-4-(methylsulfonyl)phenoxy]phenyl}benzenesulfonamide;-   3-fluoro-N-{3-[2-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-4-(methylsulfonyl)phenoxy]phenyl}benzenesulfonamide;-   4-fluoro-N-{3-[2-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-4-(methylsulfonyl)phenoxy]phenyl}benzenesulfonamide;-   3-methoxy-N-{3-[2-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-4-(methylsulfonyl)phenoxy]phenyl}benzenesulfonamide;-   N-{3-[2-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-4-(methylsulfonyl)phenoxy]phenyl}-4-nitrobenzenesulfonamide;-   4-acetyl-N-{3-[2-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-4-(methylsulfonyl)phenoxy]phenyl}benzenesulfonamide;-   5-(dimethylamino)-N-{3-[2-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-4-(methylsulfonyl)phenoxy]phenyl}naphthalene-1-sulfonamide;-   N-{3-[2-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-4-(methylsulfonyl)phenoxy]phenyl}-4-(propan-2-yl)benzenesulfonamide;-   2,4-difluoro-N-{3-[2-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-4-(methylsulfonyl)phenoxy]phenyl}benzenesulfonamide;-   3-(difluoromethoxy)-N-{3-[2-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-4-(methylsulfonyl)phenoxy]phenyl}benzenesulfonamide;-   N-{3-[2-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-4-(methylsulfonyl)phenoxy]phenyl}cyclopropanesulfonamide;-   3-methyl-N-{3-[2-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-4-(methylsulfonyl)phenoxy]phenyl}benzenesulfonamide;-   N-{3-[2-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-4-(methylsulfonyl)phenoxy]phenyl}-3-nitrobenzenesulfonamide;-   4-fluoro-2-methyl-N-{3-[2-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-4-(methylsulfonyl)phenoxy]phenyl}benzenesulfonamide;-   3,4-dimethoxy-N-{3-[2-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-4-(methylsulfonyl)phenoxy]phenyl}benzenesulfonamide;-   N-{3-[2-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-4-(methylsulfonyl)phenoxy]phenyl}-4-(methylsulfonyl)benzenesulfonamide;-   2-cyano-N-{3-[2-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-4-(methylsulfonyl)phenoxy]phenyl}benzenesulfonamide;-   4-cyano-N-{3-[2-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-4-(methylsulfonyl)phenoxy]phenyl}benzenesulfonamide;-   3-cyano-N-{3-[2-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-4-(methylsulfonyl)phenoxy]phenyl}benzenesulfonamide;-   2-chloro-4-fluoro-N-{3-[2-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-4-(methylsulfonyl)phenoxy]phenyl}benzenesulfonamide;-   1-methyl-N-{3-[2-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-4-(methylsulfonyl)phenoxy]phenyl}-1H-imidazole-4-sulfonamide;-   3-[({3-[2-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-4-(methylsulfonyl)phenoxy]phenyl}amino)methyl]benzonitrile;-   4-[({3-[2-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-4-(methylsulfonyl)phenoxy]phenyl}amino)methyl]benzonitrile;-   4-[2-{3-[(4-fluorobenzyl)amino]phenoxy}-5-(methylsulfonyl)phenyl]-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one;-   4-{2-[(2,2-difluorocyclopropyl)methoxy]-5-(ethylsulfonyl)phenyl}-2-[3-(dimethylamino)prop-1-yn-1-yl]-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one;-   4-[2-{3-[(2-methoxyethyl)amino]phenoxy}-5-(methylsulfonyl)phenyl]-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one;-   6-methyl-4-[5-(methylsulfonyl)-2-{3-[(tetrahydrofuran-2-ylmethyl)amino]phenoxy}phenyl]-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one;-   4-[2-{3-[(3-methoxybenzyl)amino]phenoxy}-5-(methylsulfonyl)phenyl]-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one;-   4-[2-{3-[(2-fluorobenzyl)amino]phenoxy}-5-(methylsulfonyl)phenyl]-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one;-   4-[2-{3-[(3-fluorobenzyl)amino]phenoxy}-5-(methylsulfonyl)phenyl]-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one;-   6-methyl-4-[5-(methylsulfonyl)-2-(3-{[3-(trifluoromethoxy)benzyl]amino}phenoxy)phenyl]-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one;-   4-[2-{3-[(2,4-dimethylbenzyl)amino]phenoxy}-5-(methylsulfonyl)phenyl]-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one;-   2-[({3-[2-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-4-(methylsulfonyl)phenoxy]phenyl}amino)methyl]benzonitrile;-   4-[2-{3-[(2-chloro-4-fluorobenzyl)amino]phenoxy}-5-(methylsulfonyl)phenyl]-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one;-   4-[2-{3-[(3,5-difluorobenzyl)amino]phenoxy}-5-(methylsulfonyl)phenyl]-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one;-   4-{2-[3-({4-[3-(dimethylamino)propoxy]benzyl}amino)phenoxy]-5-(methylsulfonyl)phenyl}-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one;-   4-[2-(3-{[3-(dimethylamino)benzyl]amino}phenoxy)-5-(methylsulfonyl)phenyl]-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one;-   4-[2-{3-[(2,3-dihydro-1,4-benzodioxin-6-ylmethyl)amino]phenoxy}-5-(methylsulfonyl)phenyl]-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one;-   6-methyl-4-[5-(methylsulfonyl)-2-{3-[(tetrahydrofuran-3-ylmethyl)amino]phenoxy}phenyl]-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one;-   N-{4-[({3-[2-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-4-(methylsulfonyl)phenoxy]phenyl}amino)methyl]phenyl}acetamide;-   4-[2-{3-[(4-methoxybenzyl)amino]phenoxy}-5-(methylsulfonyl)phenyl]-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one;-   4-[2-{3-[(cyclopropylmethyl)amino]phenoxy}-5-(methylsulfonyl)phenyl]-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one;-   4-[2-{3-[(2-cyclopentylethyl)amino]phenoxy}-5-(methylsulfonyl)phenyl]-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one;-   4-[2-{4-chloro-2-[3-(morpholin-4-yl)prop-1-yn-1-yl]phenoxy}-5-(ethylsulfonyl)phenyl]-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one;-   4-[2-{4-chloro-2-[3-(morpholin-4-yl)propyl]phenoxy}-5-(ethylsulfonyl)phenyl]-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one;-   6-methyl-4-[5-(methylsulfonyl)-2-{[1-(phenylsulfonyl)piperidin-4-yl]amino}phenyl]-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one;-   4-[2-({1-[(dimethylamino)acetyl]piperidin-4-yl}amino)-5-(methylsulfonyl)phenyl]-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one;-   6-methyl-4-[2-({1-[3-(methylsulfanyl)propyl]piperidin-4-yl}amino)-5-(methylsulfonyl)phenyl]-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one;-   N-{4-[(4-{[2-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-4-(methylsulfonyl)phenyl]amino}piperidin-1-yl)methyl]phenyl}acetamide;-   6-methyl-4-[5-(methylsulfonyl)-2-{[1-(3,4,5-trimethoxybenzyl)piperidin-4-yl]amino}phenyl]-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one;-   6-methyl-4-[5-(methylsulfonyl)-2-{[1-(thiophen-2-ylmethyl)piperidin-4-yl]amino}phenyl]-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one;-   4-{2-[(1-{4-[3-(dimethylamino)propoxy]benzyl}piperidin-4-yl)amino]-5-(methylsulfonyl)phenyl}-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one;-   6-methyl-4-[2-({1-[(methylsulfanyl)acetyl]piperidin-4-yl}amino)-5-(methylsulfonyl)phenyl]-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one;-   6-methyl-4-[5-(methylsulfonyl)-2-({1-[3-(2,3,4-trimethoxyphenyl)propanoyl]piperidin-4-yl}amino)phenyl]-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one;-   1-[(4-{[2-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-4-(methylsulfonyl)phenyl]amino}piperidin-1-yl)carbonyl]cyclopropanecarboxamide;-   4-[2-({1-[(4-methoxycyclohexyl)carbonyl]piperidin-4-yl}amino)-5-(methylsulfonyl)phenyl]-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one;-   4-[2-{[1-(methoxyacetyl)piperidin-4-yl]amino}-5-(methylsulfonyl)phenyl]-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one;-   6-methyl-4-[2-({1-[(4-methylpiperazin-1-yl)acetyl]piperidin-4-yl}amino)-5-(methylsulfonyl)phenyl]-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one;-   6-methyl-4-[5-(methylsulfonyl)-2-{[1-(pyrrolidin-1-ylacetyl)piperidin-4-yl]amino}phenyl]-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one;-   4-[2-({1-[(2-methoxyethoxy)acetyl]piperidin-4-yl}amino)-5-(methylsulfonyl)phenyl]-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one;-   6-methyl-4-[5-(methylsulfonyl)-2-({1-[3-(morpholin-4-yl)propanoyl]piperidin-4-yl}amino)phenyl]-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one;-   6-methyl-4-[2-({1-[(4-methylphenyl)acetyl]piperidin-4-yl}amino)-5-(methylsulfonyl)phenyl]-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one;-   4-[2-{[1-(benzylsulfonyl)piperidin-4-yl]amino}-5-(methylsulfonyl)phenyl]-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one;-   6-methyl-4-{5-(methylsulfonyl)-2-[(1-{[(E)-2-phenylethenyl]sulfonyl}piperidin-4-yl)amino]phenyl}-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one;-   N-{4-[(4-{[2-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-4-(methylsulfonyl)phenyl]amino}piperidin-1-yl)sulfonyl]phenyl}acetamide;-   4-[2-({1-[(4-methoxyphenyl)sulfonyl]piperidin-4-yl}amino)-5-(methylsulfonyl)phenyl]-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one;-   3-[(4-{[2-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-4-(methylsulfonyl)phenyl]amino}piperidin-1-yl)sulfonyl]benzonitrile;-   6-methyl-4-[5-(methylsulfonyl)-2-{[1-(thiophen-2-ylsulfonyl)piperidin-4-yl]amino}phenyl]-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one;-   6-methyl-4-[5-(methylsulfonyl)-2-({trans-4-[(thiophen-2-ylmethyl)amino]cyclohexyl}amino)phenyl]-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one;-   N-(4-{[(trans-4-{[2-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-4-(methylsulfonyl)phenyl]amino}cyclohexyl)amino]methyl}phenyl)acetamide;-   4-[2-({trans-4-[(2,4-difluorobenzyl)amino]cyclohexyl}amino)-5-(methylsulfonyl)phenyl]-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one;-   6-methyl-4-[5-(methylsulfonyl)-2-({trans-4-[(naphthalen-2-ylmethyl)amino]cyclohexyl}amino)phenyl]-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one;-   4-[2-({trans-4-[(2-methoxyethyl)amino]cyclohexyl}amino)-5-(methylsulfonyl)phenyl]-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one;-   6-methyl-4-{2-[(trans-4-{[3-(methylsulfanyl)propyl]amino}cyclohexyl)amino]-5-(methylsulfonyl)phenyl}-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one;-   4-[2-({trans-4-[(4-chlorobenzyl)amino]cyclohexyl}amino)-5-(methylsulfonyl)phenyl]-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one,-   4-[2-(2,4-difluorophenoxy)-5-(methylsulfonyl)phenyl]-6-methyl-2-{[4-(1,3-thiazol-2-yl)piperazin-1-yl]methyl}-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one;-   2-[(4-cyclopropylpiperazin-1-yl)methyl]-4-[2-(2,4-difluorophenoxy)-5-(methylsulfonyl)phenyl]-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one;-   4-[2-(2,4-difluorophenoxy)-5-(methylsulfonyl)phenyl]-6-methyl-2-{[4-(tetrahydro-2H-pyran-4-yl)piperazin-1-yl]methyl}-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one;-   4-[2-(2,4-difluorophenoxy)-5-(ethylsulfonyl)phenyl]-6-methyl-2-(1-phenyl-1H-pyrazol-5-yl)-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one;-   4-[2-(2,4-difluorophenoxy)-5-(ethylsulfonyl)phenyl]-6-methyl-2-[2-(morpholin-4-yl)pyridin-3-yl]-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one;-   4-[2-{2-[(cyclopropylmethyl)amino]-6-methylphenoxy}-5-(ethylsulfonyl)phenyl]-N-ethyl-6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-2-carboxamide;-   4-[2-(2-chloro-6-methylphenoxy)-5-(ethylsulfonyl)phenyl]-N-(cyanomethyl)-6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-2-carboxamide;-   4-[2-(2-chloro-6-methylphenoxy)-5-(ethylsulfonyl)phenyl]-6-methyl-N-[1-(methylamino)-1-oxopropan-2-yl]-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-2-carboxamide;-   4-[2-(2-chloro-6-methylphenoxy)-5-(ethylsulfonyl)phenyl]-6-methyl-7-oxo-N-[2-oxo-2-(piperidin-1-yl)ethyl]-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-2-carboxamide;-   4-[2-(2-chloro-6-methylphenoxy)-5-(ethylsulfonyl)phenyl]-N-(2-cyanoethyl)-6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-2-carboxamide;-   4-[2-(2-chloro-6-methylphenoxy)-5-(ethylsulfonyl)phenyl]-6-methyl-N-[2-(methylamino)-2-oxoethyl]-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-2-carboxamide;-   4-[2-(2,4-difluorophenoxy)-5-(methylsulfonyl)phenyl]-6-methyl-2-{[4-(1-methylpiperidin-4-yl)piperazin-1-yl]methyl}-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one;-   4-[2-(2,4-difluorophenoxy)-5-(methylsulfonyl)phenyl]-6-methyl-2-{[4-(pyridin-2-yl)-1,4-diazepan-1-yl]methyl}-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one;-   4-[2-(2,4-difluorophenoxy)-5-(methylsulfonyl)phenyl]-2-{[3-(furan-2-yl)morpholin-4-yl]methyl}-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one;-   4-[2-(2,4-difluorophenoxy)-5-(methylsulfonyl)phenyl]-2-{[4-(3,5-dimethyl-4H-1,2,4-triazol-4-yl)piperidin-1-yl]methyl}-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one;-   4-[2-(2,4-difluorophenoxy)-5-(methylsulfonyl)phenyl]-2-{[3-(3,5-dimethyl-1H-pyrazol-1-yl)azetidin-1-yl]methyl}-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one;-   4-[2-(2,4-difluorophenoxy)-5-(methylsulfonyl)phenyl]-6-methyl-2-{[4-(morpholin-4-yl)piperidin-1-yl]methyl}-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one;-   4-[2-(2,4-difluorophenoxy)-5-(methylsulfonyl)phenyl]-6-methyl-2-{[2-(3-methyl-1,2,4-oxadiazol-5-yl)pyrrolidin-1-yl]methyl}-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one;-   4-[2-(2,4-difluorophenoxy)-5-(methylsulfonyl)phenyl]-6-methyl-2-{[4-(pyridin-2-yl)piperazin-1-yl]methyl}-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one;-   N-ethyl-4-[5-(ethylsulfonyl)-2-{2-methyl-6-[(tetrahydrofuran-3-ylmethyl)amino]phenoxy}phenyl]-6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-2-carboxamide;-   (2E)-3-{4-[2-(2,6-dimethylphenoxy)-5-(ethylsulfonyl)phenyl]-6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-2-yl}-N-ethylprop-2-enamide;-   2-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)-4-[2-(2,6-dimethylphenoxy)-5-(methylsulfonyl)phenyl]-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one;-   2-(3-cyclohexyl-1,2,4-oxadiazol-5-yl)-4-[2-(2,6-dimethylphenoxy)-5-(methylsulfonyl)phenyl]-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one;-   4-[2-(2,6-dimethylphenoxy)-5-(methylsulfonyl)phenyl]-6-methyl-2-(3-phenyl-1,2,4-oxadiazol-5-yl)-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one;-   4-[2-(2,6-dimethylphenoxy)-5-(methylsulfonyl)phenyl]-6-methyl-2-[3-(pyridin-3-yl)-1,2,4-oxadiazol-5-yl]-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one;-   4-[2-(2,6-dimethylphenoxy)-5-(methylsulfonyl)phenyl]-6-methyl-2-[3-(pyridin-2-yl)-1,2,4-oxadiazol-5-yl]-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one;-   4-[2-(2,6-dimethylphenoxy)-5-(methylsulfonyl)phenyl]-6-methyl-2-[3-(pyrazin-2-yl)-1,2,4-oxadiazol-5-yl]-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one;-   4-[2-(2,6-dimethylphenoxy)-5-(methylsulfonyl)phenyl]-6-methyl-2-[3-(tetrahydro-2H-pyran-4-yl)-1,2,4-oxadiazol-5-yl]-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one;-   4-[2-(2,6-dimethylphenoxy)-5-(methylsulfonyl)phenyl]-6-methyl-2-[3-(1,3-thiazol-4-yl)-1,2,4-oxadiazol-5-yl]-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one;-   N-[2-(diethylamino)-2-methylpropyl]-4-[2-(2,6-dimethylphenoxy)-5-(methylsulfonyl)phenyl]-6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-2-carboxamide;-   N-[4-(diethylamino)butyl]-4-[2-(2,6-dimethylphenoxy)-5-(methylsulfonyl)phenyl]-6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-2-carboxamide;-   N-ethyl-4-{5-(ethylsulfonyl)-2-[2-methyl-6-(1H-pyrazol-1-ylmethyl)phenoxy]phenyl}-6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-2-carboxamide;-   N-ethyl-4-{5-(ethylsulfonyl)-2-[2-methyl-6-(morpholin-4-ylmethyl)phenoxy]phenyl}-6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-2-carboxamide;-   N-ethyl-4-{5-(ethylsulfonyl)-2-[2-methyl-6-(piperidin-1-ylmethyl)phenoxy]phenyl}-6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-2-carboxamide;-   N-ethyl-4-{5-(ethylsulfonyl)-2-[2-methyl-6-(2-phenylethyl)phenoxy]phenyl}-6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-2-carboxamide;-   4-[2-(cyclohexyloxy)-5-(ethylsulfonyl)phenyl]-6-methyl-2-[1-(piperidin-4-yl)-1H-pyrazol-4-yl]-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one;-   N-ethyl-4-{5-(ethylsulfonyl)-2-[2-(1H-imidazol-1-ylmethyl)-6-methylphenoxy]phenyl}-6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-2-carboxamide;-   N-ethyl-4-[5-(ethylsulfonyl)-2-{2-methyl-6-[(2-oxopyrrolidin-1-yl)methyl]phenoxy}phenyl]-6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-2-carboxamide;-   4-[2-{2-[(1,1-dioxido-1,2-thiazolidin-2-yl)methyl]-6-methylphenoxy}-5-(ethylsulfonyl)phenyl]-N-ethyl-6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-2-carboxamide;-   4-[2-(2,6-dimethylphenoxy)-4-{[2-(methylamino)-2-oxoethyl](pyridin-2-ylmethyl)carbamoyl}phenyl]-N-ethyl-6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-2-carboxamide;-   4-[2-(2,6-dimethylphenoxy)-4-{methyl[1-(propanoyloxy)piperidin-4-yl]carbamoyl}phenyl]-N-ethyl-6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-2-carboxamide;-   1-({4-[2-(2,4-difluorophenoxy)-5-(methylsulfonyl)phenyl]-6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-2-yl}methyl)-N,N-dimethyl-4-(2-oxopyrrolidin-1-yl)piperidine-4-carboxamide;-   4-[2-(2,4-difluorophenoxy)-5-(methylsulfonyl)phenyl]-6-methyl-2-{[3-(1H-1,2,4-triazol-1-yl)azetidin-1-yl]methyl}-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one;-   N-ethyl-4-[5-(ethylsulfonyl)-2-{2-methyl-6-[(2-oxoazetidin-1-yl)methyl]phenoxy}phenyl]-6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-2-carboxamide;-   N-ethyl-4-[5-(ethylsulfonyl)-2-{2-methyl-6-[(2-oxopyridin-1    (2H)-yl)methyl]phenoxy}phenyl]-6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-2-carboxamide;-   3-[({4-[2-(2,4-difluorophenoxy)-5-(methylsulfonyl)phenyl]-6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-2-yl}methyl)amino]propanamide;-   methyl    3-[{3-(2,6-dimethylphenoxy)-4-[2-(ethylcarbamoyl)-6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl]benzoyl}(phenyl)amino]propanoate;-   4-[4-{benzyl[3-(morpholin-4-yl)propyl]carbamoyl}-2-(2,6-dimethylphenoxy)phenyl]-N-ethyl-6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-2-carboxamide;-   4-[4-{(3,4-dichlorophenyl)[2-(thiomorpholin-4-yl)ethyl]carbamoyl}-2-(2,6-dimethylphenoxy)phenyl]-N-ethyl-6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-2-carboxamide;    and-   N-{4-(2,4-difluorophenoxy)-3-[2-(3-methoxyprop-1-yn-1-yl)-6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl]phenyl}ethanesulfonamide;    or a pharmaceutically acceptable salt thereof.

Compounds of formula (I) may be used in the form of pharmaceuticallyacceptable salts. The phrase “pharmaceutically acceptable salt” meansthose salts which are, within the scope of sound medical judgement,suitable for use in contact with the tissues of humans and lower animalswithout undue toxicity, irritation, allergic response and the like andare commensurate with a reasonable benefit/risk ratio.

Pharmaceutically acceptable salts have been described in S. M. Berge etal. J. Pharmaceutical Sciences, 1977, 66:1-19.

Compounds of formula (I) may contain either a basic or an acidicfunctionality, or both, and can be converted to a pharmaceuticallyacceptable salt, when desired, by using a suitable acid or base. Thesalts may be prepared in situ during the final isolation andpurification of the compounds of the invention.

Examples of acid addition salts include, but are not limited to acetate,adipate, alginate, citrate, aspartate, benzoate, benzenesulfonate,bisulfate, butyrate, camphorate, camphorsulfonate, digluconate,glycerophosphate, hemisulfate, heptanoate, hexanoate, fumarate,hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethansulfonate(isothionate), lactate, malate, maleate, methanesulfonate, nicotinate,2-naphthalenesulfonate, oxalate, palmitoate, pectinate, persulfate,3-phenylpropionate, picrate, pivalate, propionate, succinate, tartrate,thiocyanate, phosphate, glutamate, bicarbonate, p-toluenesulfonate andundecanoate. Also, the basic nitrogen-containing groups can bequaternized with such agents as lower alkyl halides such as, but notlimited to, methyl, ethyl, propyl, and butyl chlorides, bromides andiodides; dialkyl sulfates like dimethyl, diethyl, dibutyl and diamylsulfates; long chain halides such as, but not limited to, decyl, lauryl,myristyl and stearyl chlorides, bromides and iodides; arylalkyl halideslike benzyl and phenethyl bromides and others. Water or oil-soluble ordispersible products are thereby obtained. Examples of acids which maybe employed to form pharmaceutically acceptable acid addition saltsinclude such inorganic acids as hydrochloric acid, hydrobromic acid,sulfuric acid, and phosphoric acid and such organic acids as aceticacid, fumaric acid, maleic acid, 4-methylbenzenesulfonic acid, succinicacid and citric acid.

Basic addition salts may be prepared in situ during the final isolationand purification of compounds of this invention by reacting a carboxylicacid-containing moiety with a suitable base such as, but not limited to,the hydroxide, carbonate or bicarbonate of a pharmaceutically acceptablemetal cation or with ammonia or an organic primary, secondary ortertiary amine. Pharmaceutically acceptable salts include, but are notlimited to, cations based on alkali metals or alkaline earth metals suchas, but not limited to, lithium, sodium, potassium, calcium, magnesiumand aluminum salts and the like and nontoxic quaternary ammonia andamine cations including ammonium, tetramethylammonium,tetraethylammonium, methylamine, dimethylamine, trimethylamine,triethylamine, diethylamine, ethylamine and the like. Other examples oforganic amines useful for the formation of base addition salts includeethylenediamine, ethanolamine, diethanolamine, piperidine, piperazineand the like.

The term “pharmaceutically acceptable prodrug” or “prodrug” as usedherein, represents those prodrugs of the compounds of the presentinvention which are, within the scope of sound medical judgement,suitable for use in contact with the tissues of humans and lower animalswithout undue toxicity, irritation, allergic response, and the like,commensurate with a reasonable benefit/risk ratio, and effective fortheir intended use.

The present invention contemplates compounds of formula (I) formed bysynthetic means or formed by in vivo biotransformation of a prodrug.

Compounds described herein can exist in unsolvated as well as solvatedforms, including hydrated forms, such as hemi-hydrates. In general, thesolvated forms, with pharmaceutically acceptable solvents such as waterand ethanol among others are equivalent to the unsolvated forms for thepurposes of the invention.

General Synthesis

The compounds described herein, including compounds of general formula(I) and specific examples, can be prepared by methodologies known in theart, for example, through the reaction schemes depicted in schemes 1-4.The variables A¹, A², A³, A⁴, R^(x), R^(y), R^(x1), L¹, G¹, R^(xa),R^(xb), R^(xc), R^(bx1), R^(cx1), G^(x1), and G^(x2) used in thefollowing schemes have the meanings as set forth in the summary anddetailed description sections, unless otherwise noted. PG denotes aprotecting group such as, for example, benzyl or tosyl group. Suitableprotecting groups and the methods for protecting and deprotectingdifferent substituents using such suitable protecting groups are wellknown to those skilled in the art; examples of which can be found in T.Greene and P. Wuts, Protecting Groups in Organic Synthesis (3^(rd) ed.),John Wiley & Sons, NY (1999), which is incorporated herein by referencein its entirety.

Abbreviations used in the descriptions of the schemes and the specificexamples have the following meanings: DIPEA for diisopropylethylamine,DMA for N,N-dimethylacetamide, DMSO for dimethyl sulfoxide, dppf for1,1′-bis(diphenylphosphino)ferrocene, HATU forO-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate; HPLC for High Performance Liquid chromatography,Prep HPLC for Preparative High Performance Liquid chromatography, MeOHfor methanol, Pd₂(dba)₃ for tris(dibenzylideneacetone)dipalladium(0),PdCl₂(PPh₃)₂ for bis(triphenylphosphine)palladium(II) dichloride, TFAfor trifluoroacetic acid, THF for tetrahydrofuran, and tosyl fortoluenesulfonyl.

Compounds of general formula (I) may be prepared (a) by treating an arylhalide, an aryl mesylate, or an aryl triflate with an aryl boronic acidor derivatives thereof (e.g. boronic esters) under Suzuki couplingcondition (N. Miyama and A. Suzuki, Chem. Rev. 1995, 95:2457-2483, J.Organomet. Chem. 1999, 576:147-148), and (b) removal of the protectinggroup (PG), as illustrated in Scheme 1. Thus coupling of compounds offormula (1) wherein R¹⁰¹ is Br, Cl, mesylate, or triflate with compoundsof formula (2) wherein R¹⁰² is boronic acid or derivatives thereof (e.g.boronic esters), or coupling of (1) wherein R¹⁰¹ is boronic acid orderivatives thereof (e.g. boronic esters) with compounds (2) whereinR¹⁰² is Br, Cl, mesylate, or triflate, provides intermediates of formula(3). Generally, the coupling reaction is effected in the presence of apalladium catalyst and a base, and optionally in the presence of aligand, and in a suitable solvent at elevated temperature (for example,at a temperature ranging from about 80° C. to about 150° C.). Thereaction may be facilitated by microwave irradiation. Examples of thepalladium catalyst include, but are not limited to,tetrakis(triphenylphosphine)palladium(0),tris(dibenzylideneacetone)dipalladium(0), and palladium(II)acetate.Examples of suitable bases that may be employed include, but are notlimited to, carbonates or phosphates of sodium, potassium, and cesium;and cesium fluoride. Examples of suitable ligands include, but are notlimited to,1,3,5,7-tetramethyl-6-phenyl-2,4,8-trioxa-6-phosphaadamantane,2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl (X-phos), and1,1′-bis(diphenylphosphanyl) ferrocene. Non-limiting examples ofsuitable solvent include methanol, dimethoxyethane,N,N-dimethylformamide, dimethylsulfoxide, dioxane, tetrahydrofuran, andwater, or a mixture thereof.

Alternatively, treatment of formula (1) wherein R¹⁰¹ is Br, Cl, ortriflate with boronic acid of formula (4), followed by displacement ofthe fluoride atom in (4) with an appropriate alcohol or amine of formulaG¹-L¹-H wherein L¹ is O or NH, provides compounds of formula (3) orformula (I) wherein R^(x) is hydrogen.

Displacement of the fluorine with an alcohol or amine may be achieved ina solvent such as, but not limited to, dimethylsulfoxide,dimethylformamide, dioxane, or tetrahydrofuran, and in the presence of abase such as, but not limited to, cesium carbonate, potassium carbonate,or sodium hydride and at a temperature from about 40° C. to about 120°C.

The protecting group (PG) may be removed in situ during the displacementreaction or the coupling conditions described above.

Alternatively, removal of the protecting group (PG) to afford compoundsof general formula (I) wherein R^(x) is hydrogen can be accomplishedusing reaction conditions known generally to one skilled in the art, ormodifications thereof. For example, the tosyl protecting group can beremoved in the presence of a base such as, but not limited to, cesiumcarbonate, sodium hydroxide, or sodium hydride. The reaction isgenerally performed in the presence of a suitable solvent such as, butnot limited to, dimethylsulfoxide, methanol, or tetrahydrofuran, and ata temperature of about 40° C. to about 120° C. The benzyl protectinggroup may be removed by hydrogenation in the presence of a catalyst suchas, but not limited to, palladium on carbon and under hydrogenatmosphere. The reaction is typically performed in the presence of asolvent such as, but not limited to, methanol or ethyl acetate, and atabout room temperature.

Removal of the (trimethylsilyl)ethoxy)methyl protecting group can beachieved by treatment with a base such as, but not limited to, cesiumcarbonate or sodium hydride, or with a fluoride reagent such as, but notlimited to, TBAF (tetrabutylammonium fluoride). The reaction isgenerally performed in the presence of a suitable solvent such as, butnot limited to, dimethylsulfoxide, ethanol, or tetrahydrofuran, and at atemperature of about 40° C. to about 120° C. Removal of the(trimethylsilyl)ethoxy)methyl protecting group can also be achieved bytreatment with an mild acid such as but not limited to, aqueoushydrochloric acid. The reaction is generally performed in the presenceof a suitable solvent such as, but not limited to, ethanol, or methanol,and at a temperature of about 25° C. to about 80° C.

Compounds of formula (1) wherein R^(x1) is hydrogen may be prepared bygeneral synthetic methods as shown in Scheme 2.

Treatment of compounds of formula (6) wherein halo is Br, Cl, or I, with1,1-dimethoxy-N,N-dimethylmethanamine at elevated temperature (e.g.about 60° C. to about 100° C.), in the absence or presence of a base,and in a solvent such as, but not limited to, N,N-dimethylformamide,provides compounds of formula (7). Examples of suitable bases include,but are not limited to, lithium or sodium methanolate. Catalytichydrogenation of (7) in the presence of a catalyst such as, but notlimited to, Raney-Nickel and under hydrogen atmosphere (about 30 psi)and in a solvent such as, but not limited to, ethyl acetate, at aboutroom temperature generally affords compounds of formula (8). Protectionof the nitrogen atom with protecting group such as, but not limited to,benzyl, tosyl, and (trimethylsilyl)ethoxy)methyl group can be derivedfrom reaction with an appropriate halide in the presence of a strongbase such as, for example, sodium hydride, to provide compounds offormula (9).

Treatment of (9) with an acid such as, for example, hydrochloric acid orhydrobromic acid and in a solvent such as, for example, dioxane orwater, at about 40° C. to about 100° C., provides compounds of formula(10).

Alkylation of (10) with a halide or mesylate, in the presence of a basesuch as, for example, sodium hydride, cesium carbonate, or potassiumcarbonate, and in a solvent such as, for example, dimethylformamide ordimethylsulfoxide at a temperature of about 0° C. to about 50° C.provides compounds of formula (11).

Treatment of the compounds of formula (11) with4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) affordscompounds of formula (12). In general, the conversion may be facilitatedby a palladium catalyst such as, for example,tetrakis(triphenylphosphine)palladium(0),tris(dibenzylideneacetone)dipalladium(0), or palladium(II)acetate, anoptional ligand such as, but not limited to,2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl,2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl (X-phos), or1,1′-bis(diphenylphosphanyl) ferrocene, and a base such as, but notlimited to, carbonates, acetates, or phosphates. of sodium, potassium,or cesium; and cesium fluoride. Non-limiting examples of suitablesolvents include methanol, dimethoxyethane, N,N-dimethylformamide,dimethylsulfoxide, dioxane, tetrahydropyran, and water, or a mixturethereof.

Scheme 3 demonstrates a general approach to the preparation of compoundsof formula (1) wherein R¹⁰¹ is boronic acid derivative, and R^(x1) is—COOEt.

An ester of formula (14) may be obtained from (a) treatment of (6) withdiethyl oxalate in the presence of a base such as, but not limited to,potassium ethoxide or sodium ethoxide, in a solvent such as, but notlimited to, ethanol, dioxane, or diethyl ether, and at a temperature ofabout 40° C. to about 80° C.; and (b) cyclization of the resultingintermediates (13) in the presence of iron and in ethanol and aceticacid, at a temperature of about 80° C. to about 100° C. Conversion of(14) to (18) can be achieved by employing reaction conditions discussedin Scheme 2.

Scheme 4 illustrates a general approach to the preparation of compoundsof formula (I) wherein R^(x1) is -G^(x1)-G^(x2), —C(O)N(R^(xa))(R^(x)),or C₁ alkyl substituted with one —NR^(xa)R^(xb) group.

Palladium coupling of compounds (18) with compounds (2) wherein R¹⁰² isBr, Cl, mesylate, or triflate, followed by removal of the protectinggroup (either in situ or treatment with a base) using reactionconditions described in Scheme 2, provides compounds (19). Hydrolysis ofthe esters (19) affords the corresponding acids (20) which may becoupled with an appropriate amines of formula NH(R^(xa))(R^(xb)) toprovide the amides (24). Amides (24) may also be prepared directly fromthe reaction of the esters (19) with an amines of formulaNH(R^(a))(R^(b)). Reduction of the acids (20) followed by oxidationprovides the aldehydes (22). Reductive amination of (22) provides aminesof formula (23). Amines (23) may also be obtained from directdisplacement of the alcohols (22) by amines of formulaNH(R^(xa))(R^(xb)).

Compounds of general formula (I) wherein R^(x1) is —C(O)NR^(bx1)R^(cx1)or C₁ alkyl substituted with one —NR^(xa)R^(xc) group may be preparedsimilarly.

Optimum reaction conditions and reaction times for each individual stepmay vary depending on the particular reactants employed and substituentspresent in the reactants used. Unless otherwise specified, solvents,temperatures and other reaction conditions may be readily selected byone of ordinary skill in the art. Specific procedures are provided inthe Synthetic Examples section. Reactions may be further processed inthe conventional manner, e.g. by eliminating the solvent from theresidue and further purified according to methodologies generally knownin the art such as, but not limited to, crystallization, distillation,extraction, trituration and chromatography. Unless otherwise described,the starting materials and reagents are either commercially available ormay be prepared by one skilled in the art from commercially availablematerials using methods described in the chemical literature.

Routine experimentations, including appropriate manipulation of thereaction conditions, reagents and sequence of the synthetic route,protection of any chemical functionality that can not be compatible withthe reaction conditions, and deprotection at a suitable point in thereaction sequence of the method are included in the scope of theinvention. Suitable protecting groups and the methods for protecting anddeprotecting different substituents using such suitable protectinggroups are well known to those skilled in the art; examples of which canbe found in T. Greene and P. Wuts, Protecting Groups in OrganicSynthesis (3^(rd) ed.), John Wiley & Sons, NY (1999), which isincorporated herein by reference in its entirety. Synthesis of thecompounds of the invention can be accomplished by methods analogous tothose described in the synthetic schemes described hereinabove and inspecific examples.

Starting materials, if not commercially available, can be prepared byprocedures selected from standard organic chemical techniques,techniques that are analogous to the synthesis of known, structurallysimilar compounds, or techniques that are analogous to the abovedescribed schemes or the procedures described in the synthetic examplessection.

When an optically active form of a compound is required, it can beobtained by carrying out one of the procedures described herein using anoptically active starting material (prepared, for example, by asymmetricinduction of a suitable reaction step), or by resolution of a mixture ofthe stereoisomers of the compound or intermediates using a standardprocedure (such as chromatographic separation, recrystallization orenzymatic resolution).

Similarly, when a pure geometric isomer of a compound is required, itcan be prepared by carrying out one of the above procedures using a puregeometric isomer as a starting material, or by resolution of a mixtureof the geometric isomers of the compound or intermediates using astandard procedure such as chromatographic separation.

Pharmaceutical Compositions

This invention also provides for pharmaceutical compositions comprisinga therapeutically effective amount of a compound of formula (I), or apharmaceutically acceptable salt thereof together with apharmaceutically acceptable carrier, diluent, or excipient therefor. Thephrase “pharmaceutical composition” refers to a composition suitable foradministration in medical or veterinary use.

The pharmaceutical compositions that comprise a compound of formula (I),alone or in combination with a second therapeutic agent, may beadministered to the subjects orally, rectally, parenterally,intracisternally, intravaginally, intraperitoneally, topically (as bypowders, ointments or drops), bucally or as an oral or nasal spray. Theterm “parenterally” as used herein, refers to modes of administrationwhich include intravenous, intramuscular, intraperitoneal, intrasternal,subcutaneous and intraarticular injection and infusion.

The term “pharmaceutically acceptable carrier” as used herein, means anon-toxic, inert solid, semi-solid or liquid filler, diluent,encapsulating material or formulation auxiliary of any type. Someexamples of materials which can serve as pharmaceutically acceptablecarriers are sugars such as, but not limited to, lactose, glucose andsucrose; starches such as, but not limited to, corn starch and potatostarch; cellulose and its derivatives such as, but not limited to,sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate;powdered tragacanth; malt; gelatin; talc; excipients such as, but notlimited to, cocoa butter and suppository waxes; oils such as, but notlimited to, peanut oil, cottonseed oil, safflower oil, sesame oil, oliveoil, corn oil and soybean oil; glycols; such a propylene glycol; esterssuch as, but not limited to, ethyl oleate and ethyl laurate; agar;buffering agents such as, but not limited to, magnesium hydroxide andaluminum hydroxide; alginic acid; pyrogen-free water; isotonic saline;Ringer's solution; ethyl alcohol, and phosphate buffer solutions, aswell as other non-toxic compatible lubricants such as, but not limitedto, sodium lauryl sulfate and magnesium stearate, as well as coloringagents, releasing agents, coating agents, sweetening, flavoring andperfuming agents, preservatives and antioxidants can also be present inthe composition, according to the judgment of the formulator.

Pharmaceutical compositions for parenteral injection comprisepharmaceutically acceptable sterile aqueous or nonaqueous solutions,dispersions, suspensions or emulsions as well as sterile powders forreconstitution into sterile injectable solutions or dispersions justprior to use. Examples of suitable aqueous and nonaqueous carriers,diluents, solvents or vehicles include water, ethanol, polyols (such asglycerol, propylene glycol, polyethylene glycol and the like), vegetableoils (such as olive oil), injectable organic esters (such as ethyloleate) and suitable mixtures thereof. Proper fluidity can bemaintained, for example, by the use of coating materials such aslecithin, by the maintenance of the required particle size in the caseof dispersions and by the use of surfactants.

These compositions may also contain adjuvants such as preservatives,wetting agents, emulsifying agents and dispersing agents. Prevention ofthe action of microorganisms can be ensured by the inclusion of variousantibacterial and antifungal agents, for example, paraben,chlorobutanol, phenol sorbic acid and the like. It may also be desirableto include isotonic agents such as sugars, sodium chloride and the like.Prolonged absorption of the injectable pharmaceutical form can bebrought about by the inclusion of agents, which delay absorption such asaluminum monostearate and gelatin.

In some cases, in order to prolong the effect of the drug, it isdesirable to slow the absorption of the drug from subcutaneous orintramuscular injection. This may be accomplished by the use of a liquidsuspension of crystalline or amorphous material with poor watersolubility. The rate of absorption of the drug then depends upon itsrate of dissolution which, in turn, may depend upon crystal size andcrystalline form. Alternatively, delayed absorption of aparenterally-administered drug form may be accomplished by dissolving orsuspending the drug in an oil vehicle.

Injectable depot forms are made by forming microencapsule matrices ofthe drug in biodegradable polymers such as polylactide-polyglycolide.Depending upon the ratio of drug to polymer and the nature of theparticular polymer employed, the rate of drug release can be controlled.Examples of other biodegradable polymers include poly(orthoesters) andpoly(anhydrides). Depot injectable formulations are also prepared byentrapping the drug in liposomes or microemulsions which are compatiblewith body tissues.

The injectable formulations can be sterilized, for example, byfiltration through a bacterial-retaining filter or by incorporatingsterilizing agents in the form of sterile solid compositions which canbe dissolved or dispersed in sterile water or other sterile injectablemedium just prior to use.

Solid dosage forms for oral administration include capsules, tablets,pills, powders and granules. In certain embodiments, solid dosage formsmay contain from 1% to 95% (w/w) of a compound of formula (I). Incertain embodiments, the compound of formula (I) may be present in thesolid dosage form in a range of from 5% to 70% (w/w). In such soliddosage forms, the active compound may be mixed with at least one inert,pharmaceutically acceptable excipient or carrier, such as sodium citrateor dicalcium phosphate and/or a) fillers or extenders such as starches,lactose, sucrose, glucose, mannitol and silicic acid; b) binders such ascarboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone,sucrose and acacia; c) humectants such as glycerol; d) disintegratingagents such as agar-agar, calcium carbonate, potato or tapioca starch,alginic acid, certain silicates and sodium carbonate; e) solutionretarding agents such as paraffin; f) absorption accelerators such asquaternary ammonium compounds; g) wetting agents such as cetyl alcoholand glycerol monostearate; h) absorbents such as kaolin and bentoniteclay and i) lubricants such as talc, calcium stearate, magnesiumstearate, solid polyethylene glycols, sodium lauryl sulfate and mixturesthereof. In the case of capsules, tablets and pills, the dosage form mayalso comprise buffering agents.

The pharmaceutical composition may be a unit dosage form. In such formthe preparation is subdivided into unit doses containing appropriatequantities of the active component. The unit dosage form can be apackaged preparation, the package containing discrete quantities ofpreparation, such as packeted tablets, capsules, and powders in vials orampules. Also, the unit dosage form can be a capsule, tablet, cachet, orlozenge itself, or it can be the appropriate number of any of these inpackaged form. The quantity of active component in a unit dosepreparation may be varied or adjusted from 0.1 mg to 1000 mg, from 1 mgto 100 mg, or from 1% to 95% (w/w) of a unit dose, according to theparticular application and the potency of the active component. Thecomposition can, if desired, also contain other compatible therapeuticagents.

The dose to be administered to a subject may be determined by theefficacy of the particular compound employed and the condition of thesubject, as well as the body weight or surface area of the subject to betreated. The size of the dose also will be determined by the existence,nature, and extent of any adverse side-effects that accompany theadministration of a particular compound in a particular subject. Indetermining the effective amount of the compound to be administered inthe treatment or prophylaxis of the disorder being treated, thephysician can evaluate factors such as the circulating plasma levels ofthe compound, compound toxicities, and/or the progression of thedisease, etc. In general, the dose equivalent of a compound is fromabout 1 rig/kg to 100 mg/kg for a typical subject.

For administration, compounds of the formula (I) may be administered ata rate determined by factors that can include, but are not limited to,the LD₅₀ of the compound, the pharmacokinetic profile of the compound,contraindicated drugs, and the side-effects of the compound at variousconcentrations, as applied to the mass and overall health of thesubject. Administration can be accomplished via single or divided doses.

The compounds utilized in the pharmaceutical method of the invention canbe administered at the initial dosage of about 0.001 mg/kg to about 100mg/kg daily. In certain embodiments, the daily dose range is from about0.1 mg/kg to about 10 mg/kg. The dosages, however, may be varieddepending upon the requirements of the subject, the severity of thecondition being treated, and the compound being employed. Determinationof the proper dosage for a particular situation is within the skill ofthe practitioner. Treatment may be initiated with smaller dosages, whichare less than the optimum dose of the compound. Thereafter, the dosageis increased by small increments until the optimum effect undercircumstances is reached. For convenience, the total daily dosage may bedivided and administered in portions during the day, if desired.

Solid compositions of a similar type may also be employed as fillers insoft and hard-filled gelatin capsules using such carriers as lactose ormilk sugar as well as high molecular weight polyethylene glycols and thelike.

The solid dosage forms of tablets, dragees, capsules, pills and granulescan be prepared with coatings and shells such as enteric coatings andother coatings well-known in the pharmaceutical formulating art. Theymay optionally contain opacifying agents and may also be of acomposition such that they release the active ingredient(s) only, orpreferentially, in a certain part of the intestinal tract, optionally,in a delayed manner. Examples of embedding compositions which can beused include polymeric substances and waxes.

The active compounds can also be in micro-encapsulated form, ifappropriate, with one or more of the above-mentioned carriers.

Liquid dosage forms for oral administration include pharmaceuticallyacceptable emulsions, solutions, suspensions, syrups and elixirs. Inaddition to the active compounds, the liquid dosage forms may containinert diluents commonly used in the art such as, for example, water orother solvents, solubilizing agents and emulsifiers such as ethylalcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzylalcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol,dimethyl formamide, oils (in particular, cottonseed, groundnut, corn,germ, olive, castor and sesame oils), glycerol, tetrahydrofurfurylalcohol, polyethylene glycols and fatty acid esters of sorbitan andmixtures thereof.

Besides inert diluents, the oral compositions may also include adjuvantssuch as wetting agents, emulsifying and suspending agents, sweetening,flavoring and perfuming agents.

Suspensions, in addition to the active compounds, may contain suspendingagents as, for example, ethoxylated isostearyl alcohols, polyoxyethylenesorbitol and sorbitan esters, microcrystalline cellulose, aluminummetahydroxide, bentonite, agar-agar, tragacanth and mixtures thereof.

Compositions for rectal or vaginal administration are preferablysuppositories which can be prepared by mixing the compounds of thisinvention with suitable non-irritating carriers or carriers such ascocoa butter, polyethylene glycol or a suppository wax which are solidat room temperature but liquid at body temperature and therefore melt inthe rectum or vaginal cavity and release the active compound.

Compounds of formula (I) may also be administered in the form ofliposomes. Liposomes generally may be derived from phospholipids orother lipid substances. Liposomes are formed by mono- or multi-lamellarhydrated liquid crystals which are dispersed in an aqueous medium. Anynon-toxic, physiologically acceptable and metabolizable lipid capable offorming liposomes can be used. The present compositions in liposome formmay contain, in addition to a compound of formula (I), stabilizers,preservatives, excipients and the like. Examples of lipids include, butare not limited to, natural and synthetic phospholipids and phosphatidylcholines (lecithins), used separately or together.

Methods to form liposomes have been described, see example, Prescott,Ed., Methods in Cell Biology, Volume XIV, Academic Press, New York, N.Y.(1976), p. 33 et seq.

Dosage forms for topical administration of a compound described hereininclude powders, sprays, ointments and inhalants. The active compoundmay be mixed under sterile conditions with a pharmaceutically acceptablecarrier and any needed preservatives, buffers or propellants which maybe required. Opthalmic formulations, eye ointments, powders andsolutions are also contemplated as being within the scope of thisinvention.

Methods of Use

The compounds of formula (I), or pharmaceutically acceptable saltsthereof, and pharmaceutical compositions comprising a compound offormula (I), or a pharmaceutically acceptable salt thereof, can beadministered to a subject suffering from a bromodomain-mediated disorderor condition. The term “administering” refers to the method ofcontacting a compound with a subject. Thus, the compounds of formula (I)may be administered by injection, that is, intravenously,intramuscularly, intracutaneously, subcutaneously, intraduodenally,parentally, or intraperitoneally. Also, the compounds described hereincan be administered by inhalation, for example, intranasally.Additionally, the compounds of formula (I) may be administeredtransdermally, topically, via implantation, transdermally, topically,and via implantation. In certain embodiments, the compounds of theformula (I) may be delivered orally. The compounds can also be deliveredrectally, bucally, intravaginally, ocularly, or by insufflation.Bromodomain-mediated disorders and conditions can be treatedprophylactically, acutely, and chronically using compounds of formula(I), depending on the nature of the disorder or condition. Typically,the host or subject in each of these methods is human, although othermammals can also benefit from the administration of a compound offormula (I).

A “bromodomain-mediated disorder or condition” is characterized by theparticipation of one or more bromodomains (e.g., BRD4) in the inception,manifestation of one or more symptoms or disease markers, severity, orprogression of a disorder or condition. Accordingly, compounds offormula (I) may be used to treat cancer, including, but not limited toacoustic neuroma, acute leukemia, acute lymphocytic leukemia, acutemyelocytic leukemia (monocytic, myeloblastic, adenocarcinoma,angiosarcoma, astrocytoma, myelomonocytic and promyelocytic), acutet-cell leukemia, basal cell carcinoma, bile duct carcinoma, bladdercancer, brain cancer, breast cancer, bronchogenic carcinoma, cervicalcancer, chondrosarcoma, chordoma, choriocarcinoma, chronic leukemia,chronic lymphocytic leukemia, chronic myelocytic (granulocytic)leukemia, chronic myelogenous leukemia, colon cancer, colorectal cancer,craniopharyngioma, cystadenocarcinoma, diffuse large B-cell lymphoma,dysproliferative changes (dysplasias and metaplasias), embryonalcarcinoma, endometrial cancer, endotheliosarcoma, ependymoma, epithelialcarcinoma, erythroleukemia, esophageal cancer, estrogen-receptorpositive breast cancer, essential thrombocythemia, Ewing's tumor,fibrosarcoma, follicular lymphoma, germ cell testicular cancer, glioma,glioblastoma, gliosarcoma, heavy chain disease, hemangioblastoma,hepatoma, hepatocellular cancer, hormone insensitive prostate cancer,leiomyosarcoma, leukemia, liposarcoma, lung cancer,lymphagioendotheliosarcoma, lymphangiosarcoma, lymphoblastic leukemia,lymphoma (Hodgkin's and non-Hodgkin's), malignancies andhyperproliferative disorders of the bladder, breast, colon, lung,ovaries, pancreas, prostate, skin and uterus, lymphoid malignancies ofT-cell or B-cell origin, leukemia, lymphoma, medullary carcinoma,medulloblastoma, melanoma, meningioma, mesothelioma, multiple myeloma,myelogenous leukemia, myeloma, myxosarcoma, neuroblastoma, NUT midlinecarcinoma (NMC), non-small cell lung cancer, oligodendroglioma, oralcancer, osteogenic sarcoma, ovarian cancer, pancreatic cancer, papillaryadenocarcinomas, papillary carcinoma, pinealoma, polycythemia vera,prostate cancer, rectal cancer, renal cell carcinoma, retinoblastoma,rhabdomyosarcoma, sarcoma, sebaceous gland carcinoma, seminoma, skincancer, small cell lung carcinoma, solid tumors (carcinomas andsarcomas), small cell lung cancer, stomach cancer, squamous cellcarcinoma, synovioma, sweat gland carcinoma, thyroid cancer,Waldenström's macroglobulinemia, testicular tumors, uterine cancer andWilms' tumor.

Further, compounds of formula (I) may be used to treat inflammatorydiseases, inflammatory conditions, and autoimmune diseases, including,but not limited to: Addison's disease, acute gout, ankylosingspondylitis, asthma, atherosclerosis, Behcet's disease, bullous skindiseases, chronic obstructive pulmonary disease (COPD), Crohn's disease,dermatitis, eczema, giant cell arteritis, glomerulonephritis, hepatitis,hypophysitis, inflammatory bowel disease, Kawasaki disease, lupusnephritis, multiple sclerosis, myocarditis, myositis, nephritis, organtransplant rejection, osteoarthritis, pancreatitis, pericarditis,Polyarteritis nodosa, pneumonitis, primary biliary cirrhosis, psoriasis,psoriatic arthritis, rheumatoid arthritis, scleritis, sclerosingcholangitis, sepsis, systemic lupus erythematosus, Takayasu's Arteritis,toxic shock, thyroiditis, type I diabetes, ulcerative colitis, uveitis,vitiligo, vasculitis, and Wegener's granulomatosis.

Compounds of formula (I), or pharmaceutically acceptable salts thereof,may be used to treat AIDS.

The compounds of formula (I) may be co-administered to a subject. Theterm “co-administered” means the administration of two or more differenttherapeutic agents or treatments (e.g., radiation treatment) that areadministered to a subject by combination in the same pharmaceuticalcomposition or separate pharmaceutical compositions. Thusco-administration involves administration at the same time of a singlepharmaceutical composition comprising two or more therapeutic agents oradministration of two or more different compositions to the same subjectat the same or different times.

The compounds of the invention can be co-administered with atherapeutically effective amount of one or more agents to treat acancer, where examples of the agents include, such as radiation,alkylating agents, angiogenesis inhibitors, antibodies, antimetabolites,antimitotics, antiproliferatives, antivirals, aurora kinase inhibitors,apoptosis promoters (for example, Bcl-xL, Bcl-w and Bfl-1) inhibitors,activators of death receptor pathway, Bcr-Abl kinase inhibitors, BiTE(Bi-Specific T cell Engager) antibodies, antibody drug conjugates,biologic response modifiers, cyclin-dependent kinase inhibitors, cellcycle inhibitors, cyclooxygenase-2 inhibitors, DVDs (dual variabledomain antibodies), leukemia viral oncogene homolog (ErbB2) receptorinhibitors, growth factor inhibitors, heat shock protein (HSP)-90inhibitors, histone deacetylase (HDAC) inhibitors, hormonal therapies,immunologicals, inhibitors of inhibitors of apoptosis proteins (IAPs),intercalating antibiotics, kinase inhibitors, kinesin inhibitors, Jak2inhibitors, mammalian target of rapamycin inhibitors, microRNA's,mitogen-activated extracellular signal-regulated kinase inhibitors,multivalent binding proteins, non-steroidal anti-inflammatory drugs(NSAIDs), poly ADP (adenosine diphosphate)-ribose polymerase (PARP)inhibitors, platinum chemotherapeutics, polo-like kinase (Plk)inhibitors, phosphoinositide-3 kinase (bromodomain) inhibitors,proteosome inhibitors, purine analogs, pyrimidine analogs, receptortyrosine kinase inhibitors, etinoids/deltoids plant alkaloids, smallinhibitory ribonucleic acids (siRNAs), topoisomerase inhibitors,ubiquitin ligase inhibitors, and the like, and in combination with oneor more of these agents.

BiTE antibodies are bi-specific antibodies that direct T-cells to attackcancer cells by simultaneously binding the two cells. The T-cell thenattacks the target cancer cell. Examples of BiTE antibodies includeadecatumumab (Micromet MT201), blinatumomab (Micromet MT103) and thelike. Without being limited by theory, one of the mechanisms by whichT-cells elicit apoptosis of the target cancer cell is by exocytosis ofcytolytic granule components, which include perforin and granzyme B. Inthis regard, Bcl-2 has been shown to attenuate the induction ofapoptosis by both perforin and granzyme B. These data suggest thatinhibition of Bcl-2 could enhance the cytotoxic effects elicited byT-cells when targeted to cancer cells (V. R. Sutton, D. L. Vaux and J.A. Trapani, J. of Immunology 1997, 158 (12), 5783).

SiRNAs are molecules having endogenous RNA bases or chemically modifiednucleotides. The modifications do not abolish cellular activity, butrather impart increased stability and/or increased cellular potency.Examples of chemical modifications include phosphorothioate groups,2′-deoxynucleotide, 2′-OCH₃-containing ribonucleotides,2′-F-ribonucleotides, 2′-methoxyethyl ribonucleotides, combinationsthereof and the like. The siRNA can have varying lengths (e.g., 10-200bps) and structures (e.g., hairpins, single/double strands, bulges,nicks/gaps, mismatches) and are processed in cells to provide activegene silencing. A double-stranded siRNA (dsRNA) can have the same numberof nucleotides on each strand (blunt ends) or asymmetric ends(overhangs). The overhang of 1-2 nucleotides can be present on the senseand/or the antisense strand, as well as present on the 5′- and/or the3′-ends of a given strand.

Multivalent binding proteins are binding proteins comprising two or moreantigen binding sites. Multivalent binding proteins are engineered tohave the three or more antigen binding sites and are generally notnaturally occurring antibodies. The term “multispecific binding protein”means a binding protein capable of binding two or more related orunrelated targets. Dual variable domain (DVD) binding proteins aretetravalent or multivalent binding proteins binding proteins comprisingtwo or more antigen binding sites. Such DVDs may be monospecific (i.e.,capable of binding one antigen) or multispecific (i.e., capable ofbinding two or more antigens). DVD binding proteins comprising two heavychain DVD polypeptides and two light chain DVD polypeptides are referredto as DVD Ig's. Each half of a DVD Ig comprises a heavy chain DVDpolypeptide, a light chain DVD polypeptide, and two antigen bindingsites. Each binding site comprises a heavy chain variable domain and alight chain variable domain with a total of 6 CDRs involved in antigenbinding per antigen binding site. Multispecific DVDs include DVD bindingproteins that bind DLL4 and VEGF, or C-met and EFGR or ErbB3 and EGFR.

Alkylating agents include altretamine, AMD-473, AP-5280, apaziquone,bendamustine, brostallicin, busulfan, carboquone, carmustine (BCNU),chlorambucil, CLORETAZINE® (laromustine, VNP 40101M), cyclophosphamide,decarbazine, estramustine, fotemustine, glufosfamide, ifosfamide,KW-2170, lomustine (CCNU), mafosfamide, melphalan, mitobronitol,mitolactol, nimustine, nitrogen mustard N-oxide, ranimustine,temozolomide, thiotepa, TREANDA® (bendamustine), treosulfan, rofosfamideand the like.

Angiogenesis inhibitors include endothelial-specific receptor tyrosinekinase (Tie-2) inhibitors, epidermal growth factor receptor (EGFR)inhibitors, insulin growth factor-2 receptor (IGFR-2) inhibitors, matrixmetalloproteinase-2 (MMP-2) inhibitors, matrix metalloproteinase-9(MMP-9) inhibitors, platelet-derived growth factor receptor (PDGFR)inhibitors, thrombospondin analogs, vascular endothelial growth factorreceptor tyrosine kinase (VEGFR) inhibitors and the like.

Antimetabolites include ALIMTA® (pemetrexed disodium, LY231514, MTA),5-azacitidine, XELODA® (capecitabine), carmofur, LEUSTAT® (cladribine),clofarabine, cytarabine, cytarabine ocfosfate, cytosine arabinoside,decitabine, deferoxamine, doxifluridine, eflornithine, EICAR(5-ethynyl-1-β-D-ribofuranosylimidazole-4-carboxamide), enocitabine,ethnylcytidine, fludarabine, 5-fluorouracil alone or in combination withleucovorin, GEMZAR® (gemcitabine), hydroxyurea, ALKERAN® (melphalan),mercaptopurine, 6-mercaptopurine riboside, methotrexate, mycophenolicacid, nelarabine, nolatrexed, ocfosfate, pelitrexol, pentostatin,raltitrexed, Ribavirin, triapine, trimetrexate, S-1, tiazofurin,tegafur, TS-1, vidarabine, UFT and the like.

Antivirals include ritonavir, hydroxychloroquine and the like.

Aurora kinase inhibitors include ABT-348, AZD-1152, MLN-8054, VX-680,Aurora A-specific kinase inhibitors, Aurora B-specific kinase inhibitorsand pan-Aurora kinase inhibitors and the like.

Bcl-2 protein inhibitors include ABT-199, AT-101 ((−)gossypol),GENASENSE® (G3139 or oblimersen (Bcl-2-targeting antisenseoligonucleotide)), IPI-194, IPI-565,N-(4-(4-((4′-chloro(1,1′-biphenyl)-2-yl)methyl)piperazin-1-yl)benzoyl)-4-(((1R)-3-(dimethylamino)-1-((phenylsulfanyl)methyl)propyl)amino)-3-nitrobenzenesulfonamide)(ABT-737),N-(4-(4-((2-(4-chlorophenyl)-5,5-dimethyl-1-cyclohex-1-en-1-yl)methyl)piperazin-1-yl)benzoyl)-4-(((1R)-3-(morpholin-4-yl)-1-((phenylsulfanyl)methyl)propyl)amino)-3-((trifluoromethyl)sulfonyl)benzenesulfonamide(ABT-263), GX-070 (obatoclax) and the like.

Bcr-Abl kinase inhibitors include DASATINIB® (BMS-354825), GLEEVEC®(imatinib) and the like.

CDK inhibitors include AZD-5438, BMI-1040, BMS-032, BMS-387, CVT-2584,flavopyridol, GPC-286199, MCS-5A, PD0332991, PHA-690509, seliciclib(CYC-202, R-roscovitine), ZK-304709 and the like.

COX-2 inhibitors include ABT-963, ARCOXIA® (etoricoxib), BEXTRA®(valdecoxib), BMS347070, CELEBREX® (celecoxib), COX-189 (lumiracoxib),CT-3, DERAMAXX® (deracoxib), JTE-522,4-methyl-2-(3,4-dimethylphenyl)-1-(4-sulfamoylphenyl-1H-pyrrole), MK-663(etoricoxib), NS-398, parecoxib, RS-57067, SC-58125, SD-8381, SVT-2016,S-2474, T-614, VIOXX® (rofecoxib) and the like.

EGFR inhibitors include EGFR antibodies, ABX-EGF, anti-EGFRimmunoliposomes, EGF-vaccine, EMD-7200, ERBITUX® (cetuximab), HR3, IgAantibodies, IRESSA® (gefitinib), TARCEVA® (erlotinib or OSI-774), TP-38,EGFR fusion protein, TYKERB® (lapatinib) and the like.

ErbB2 receptor inhibitors include CP-724-714, CI-1033 (canertinib),HERCEPTIN® (trastuzumab), TYKERB® (lapatinib), OMNITARG® (2C4,petuzumab), TAK-165, GW-572016 (ionafamib), GW-282974, EKB-569, PI-166,dHER2 (HER2 vaccine), APC-8024 (HER-2 vaccine), anti-HER/2neu bispecificantibody, B7.her2IgG3, AS HER2 trifunctional bispecfic antibodies, mABAR-209, mAB 2B-1 and the like.

Histone deacetylase inhibitors include depsipeptide, LAQ-824, MS-275,trapoxin, suberoylanilide hydroxamic acid (SAHA), TSA, valproic acid andthe like.

HSP-90 inhibitors include 17-AAG-nab, 17-AAG, CNF-101, CNF-1010,CNF-2024, 17-DMAG, geldanamycin, IPI-504, KOS-953, MYCOGRAB® (humanrecombinant antibody to HSP-90), NCS-683664, PU24FC1, PU-3, radicicol,SNX-2112, STA-9090 VER49009 and the like.

Inhibitors of inhibitors of apoptosis proteins include HGS 1029,GDC-0145, GDC-0152, LCL-161, LBW-242 and the like.

Antibody drug conjugates include anti-CD22-MC-MMAF, anti-CD22-MC-MMAE,anti-CD22-MCC-DM1, CR-011-vcMMAE, PSMA-ADC, MEDI-547, SGN-19Am SGN-35,SGN-75 and the like

Activators of death receptor pathway include TRAIL, antibodies or otheragents that target TRAIL or death receptors (e.g., DR4 and DR5) such asApomab, conatumumab, ETR2-ST01, GDC0145, (lexatumumab), HGS-1029,LBY-135, PRO-1762 and trastuzumab.

Kinesin inhibitors include Eg5 inhibitors such as AZD4877, ARRY-520;CENPE inhibitors such as GSK923295A and the like.

JAK-2 inhibitors include CEP-701 (lesaurtinib), XL019 and INCB018424 andthe like.

MEK inhibitors include ARRY-142886, ARRY-438162 PD-325901, PD-98059 andthe like.

mTOR inhibitors include AP-23573, CCI-779, everolimus, RAD-001,rapamycin, temsirolimus, ATP-competitive TORC1/TORC2 inhibitors,including PI-103, PP242, PP30, Torin 1 and the like.

Non-steroidal anti-inflammatory drugs include AMIGESIC® (salsalate),DOLOBID® (diflunisal), MOTRIN® (ibuprofen), ORUDIS® (ketoprofen),RELAFEN® (nabumetone), FELDENE® (piroxicam), ibuprofen cream, ALEVE®(naproxen) and NAPROSYN® (naproxen), VOLTAREN® (diclofenac), INDOCIN®(indomethacin), CLINORIL® (sulindac), TOLECTIN® (tolmetin), LODINE®(etodolac), TORADOL® (ketorolac), DAYPRO® (oxaprozin) and the like.

PDGFR inhibitors include C-451, CP-673, CP-868596 and the like.

Platinum chemotherapeutics include cisplatin, ELOXATIN® (oxaliplatin)eptaplatin, lobaplatin, nedaplatin, PARAPLATIN® (carboplatin),satraplatin, picoplatin and the like.

Polo-like kinase inhibitors include BI-2536 and the like.

Phosphoinositide-3 kinase (PI3K) inhibitors include wortmannin,LY294002, XL-147, CAL-120, ONC-21, AEZS-127, ETP-45658, PX-866,GDC-0941, BGT226, BEZ235, XL765 and the like.

Thrombospondin analogs include ABT-510, ABT-567, ABT-898, TSP-1 and thelike.

VEGFR inhibitors include AVASTIN® (bevacizumab), ABT-869, AEE-788,ANGIOZYME™ (a ribozyme that inhibits angiogenesis (RibozymePharmaceuticals (Boulder, Colo.) and Chiron, (Emeryville, Calif.)),axitinib (AG-13736), AZD-2171, CP-547,632, IM-862, MACUGEN (pegaptamib),NEXAVAR® (sorafenib, BAY43-9006), pazopanib (GW-786034), vatalanib(PTK-787, ZK-222584), SUTENT® (sunitinib, SU-11248), VEGF trap, ZACTIMA™(vandetanib, ZD-6474), GA101, ofatumumab, ABT-806 (mAb-806), ErbB3specific antibodies, BSG2 specific antibodies, DLL4 specific antibodiesand C-met specific antibodies, and the like.

Antibiotics include intercalating antibiotics aclarubicin, actinomycinD, amrubicin, annamycin, adriamycin, BLENOXANE® (bleomycin),daunorubicin, CAELYX® or MYOCET® (liposomal doxorubicin), elsamitrucin,epirbucin, glarbuicin, ZAVEDOS® (idarubicin), mitomycin C, nemorubicin,neocarzinostatin, peplomycin, pirarubicin, rebeccamycin, stimalamer,streptozocin, VALSTAR® (valrubicin), zinostatin and the like.

Topoisomerase inhibitors include aclarubicin, 9-aminocamptothecin,amonafide, amsacrine, becatecarin, belotecan, BN-80915, CAMPTOSAR®(irinotecan hydrochloride), camptothecin, CARDIOXANE® (dexrazoxine),diflomotecan, edotecarin, ELLENCE® or PHARMORUBICIN® (epirubicin),etoposide, exatecan, 10-hydroxycamptothecin, gimatecan, lurtotecan,mitoxantrone, orathecin, pirarbucin, pixantrone, rubitecan, sobuzoxane,SN-38, tafluposide, topotecan and the like.

Antibodies include AVASTIN® (bevacizumab), CD40-specific antibodies,chTNT-1/B, denosumab, ERBITUX® (cetuximab), HUMAX-CD4® (zanolimumab),IGF1R-specific antibodies, lintuzumab, PANOREX® (edrecolomab), RENCAREX®(WX G250), RITUXAN® (rituximab), ticilimumab, trastuzimab, CD20antibodies types I and II and the like.

Hormonal therapies include ARIMIDEX® (anastrozole), AROMASIN®(exemestane), arzoxifene, CASODEX® (bicalutamide), CETROTIDE®(cetrorelix), degarelix, deslorelin, DESOPAN® (trilostane),dexamethasone, DROGENIL® (flutamide), EVISTA® (raloxifene), AFEMA™(fadrozole), FARESTON® (toremifene), FASLODEX® (fulvestrant), FEMARA®(letrozole), formestane, glucocorticoids, HECTOROL® (doxercalciferol),RENAGEL® (sevelamer carbonate), lasofoxifene, leuprolide acetate,MEGACE® (megesterol), MIFEPREX® (mifepristone), NILANDRON™ (nilutamide),NOLVADEX® (tamoxifen citrate), PLENAXIS™ (abarelix), prednisone,PROPECIA® (finasteride), rilostane, SUPREFACT® (buserelin), TRELSTAR®(luteinizing hormone releasing hormone (LHRH)), VANTAS® (Histrelinimplant), VETORYL® (trilostane or modrastane), ZOLADEX® (fosrelin,goserelin) and the like.

Deltoids and retinoids include seocalcitol (EB1089, CB1093),lexacalcitrol (KH1060), fenretinide, PANRETIN® (aliretinoin), ATRAGEN®(liposomal tretinoin), TARGRETIN® (bexarotene), LGD-1550 and the like.

PARP inhibitors include ABT-888 (veliparib), olaparib, KU-59436,AZD-2281, AG-014699, BSI-201, BGP-15, INO-1001, ONO-2231 and the like.

Plant alkaloids include, but are not limited to, vincristine,vinblastine, vindesine, vinorelbine and the like.

Proteasome inhibitors include VELCADE® (bortezomib), MG132, NPI-0052,PR-171 and the like.

Examples of immunologicals include interferons and otherimmune-enhancing agents. Interferons include interferon alpha,interferon alpha-2a, interferon alpha-2b, interferon beta, interferongamma-1a, ACTIMMUNE® (interferon gamma-1b) or interferon gamma-n1,combinations thereof and the like. Other agents include ALFAFERONE®,(IFN-α), BAM-002 (oxidized glutathione), BEROMUN® (tasonermin), BEXXAR®(tositumomab), CAMPATH® (alemtuzumab), CTLA4 (cytotoxic lymphocyteantigen 4), decarbazine, denileukin, epratuzumab, GRANOCYTE®(lenograstim), lentinan, leukocyte alpha interferon, imiquimod, MDX-010(anti-CTLA-4), melanoma vaccine, mitumomab, molgramostim, MYLOTARG™(gemtuzumab ozogamicin), NEUPOGEN® (filgrastim), OncoVAC-CL, OVAREX®(oregovomab), pemtumomab (Y-muHMFG1), PROVENGE® (sipuleucel-T),sargaramostim, sizofilan, teceleukin, THERACYS® (BacillusCalmette-Guerin), ubenimex, VIRULIZIN® (immunotherapeutic, LorusPharmaceuticals), Z-100 (Specific Substance of Maruyama (SSM)), WF-10(Tetrachlorodecaoxide (TCDO)), PROLEUKIN® (aldesleukin), ZADAXIN®(thymalfasin), ZENAPAX® (daclizumab), ZEVALIN® (90Y-Ibritumomabtiuxetan) and the like.

Biological response modifiers are agents that modify defense mechanismsof living organisms or biological responses, such as survival, growth ordifferentiation of tissue cells to direct them to have anti-tumoractivity and include krestin, lentinan, sizofiran, picibanil PF-3512676(CpG-8954), ubenimex and the like.

Pyrimidine analogs include cytarabine (ara C or Arabinoside C), cytosinearabinoside, doxifluridine, FLUDARA® (fludarabine), 5-FU(5-fluorouracil), floxuridine, GEMZAR® (gemcitabine), TOMUDEX®(ratitrexed), TROXATYL™ (triacetyluridine troxacitabine) and the like.

Purine analogs include LANVIS® (thioguanine) and PURI-NETHOL®(mercaptopurine).

Antimitotic agents include batabulin, epothilone D (KOS-862),N-(2-((4-hydroxyphenyl)amino)pyridin-3-yl)-4-methoxybenzenesulfonamide,ixabepilone (BMS 247550), paclitaxel, TAXOTERE® (docetaxel), PNU100940(109881), patupilone, XRP-9881 (larotaxel), vinflunine, ZK-EPO(synthetic epothilone) and the like.

Ubiquitin ligase inhibitors include MDM2 inhibitors, such as nutlins,NEDD8 inhibitors such as MLN4924 and the like.

Compounds of this invention can also be used as radiosensitizers thatenhance the efficacy of radiotherapy. Examples of radiotherapy includeexternal beam radiotherapy, teletherapy, brachytherapy and sealed,unsealed source radiotherapy and the like.

Additionally, compounds having formula (I) may be combined with otherchemotherapeutic agents such as ABRAXANE™ (ABI-007), ABT-100 (famesyltransferase inhibitor), ADVEXIN® (Ad5CMV-p53 vaccine), ALTOCOR® orMEVACOR® (lovastatin), AMPLIGEN® (poly I:poly C12U, a synthetic RNA),APTOSYN® (exisulind), AREDIA® (pamidronic acid), arglabin,L-asparaginase, atamestane (1-methyl-3,17-dione-androsta-1,4-diene),AVAGE® (tazarotene), AVE-8062 (combreastatin derivative) BEC2(mitumomab), cachectin or cachexin (tumor necrosis factor), canvaxin(vaccine), CEAVAC® (cancer vaccine), CELEUK® (celmoleukin), CEPLENE®(histamine dihydrochloride), CERVARIX® (human papillomavirus vaccine),CHOP® (C: CYTOXAN® (cyclophosphamide); H: ADRIAMYCIN®(hydroxydoxorubicin); O: Vincristine (ONCOVIN®); P: prednisone), CYPAT™(cyproterone acetate), combrestatin A4P, DAB(389)EGF (catalytic andtranslocation domains of diphtheria toxin fused via a His-Ala linker tohuman epidermal growth factor) or TransMID-107R™ (diphtheria toxins),dacarbazine, dactinomycin, 5,6-dimethylxanthenone-4-acetic acid (DMXAA),eniluracil, EVIZON™ (squalamine lactate), DIMERICINE® (T4N5 liposomelotion), discodermolide, DX-8951f (exatecan mesylate), enzastaurin,EP0906 (epithilone B), GARDASIL® (quadrivalent human papillomavirus(Types 6, 11, 16, 18) recombinant vaccine), GASTRIMMUNE®, GENASENSE®,GMK (ganglioside conjugate vaccine), GVAX® (prostate cancer vaccine),halofuginone, histerelin, hydroxycarbamide, ibandronic acid, IGN-101,IL-13-PE38, IL-13-PE38QQR (cintredekin besudotox), IL-13-pseudomonasexotoxin, interferon-α, interferon-γ, JUNOVAN™ or MEPACT™ (mifamurtide),lonafarnib, 5,10-methylenetetrahydrofolate, miltefosine(hexadecylphosphocholine), NEOVASTAT® (AE-941), NEUTREXIN® (trimetrexateglucuronate), NIPENT® (pentostatin), ONCONASE® (a ribonuclease enzyme),ONCOPHAGE® (melanoma vaccine treatment), ONCOVAX® (IL-2 Vaccine),ORATHECIN™ (rubitecan), OSIDEM® (antibody-based cell drug), OVAREX® MAb(murine monoclonal antibody), paclitaxel, PANDIMEX™ (aglycone saponinsfrom ginseng comprising 20(S)protopanaxadiol (aPPD) and20(S)protopanaxatriol (aPPT)), panitumumab, PANVAC®-VF (investigationalcancer vaccine), pegaspargase, PEG Interferon A, phenoxodiol,procarbazine, rebimastat, REMOVAB® (catumaxomab), REVLIMID®(lenalidomide), RSR13 (efaproxiral), SOMATULINE® LA (lanreotide),SORIATANE® (acitretin), staurosporine (Streptomyces staurospores),talabostat (PT100), TARGRETIN® (bexarotene), TAXOPREXIN®(DHA-paclitaxel), TELCYTA® (canfosfamide, TLK286), temilifene, TEMODAR®(temozolomide), tesmilifene, thalidomide, THERATOPE® (STn-KLH), thymitaq(2-amino-3,4-dihydro-6-methyl-4-oxo-5-(4-pyridylthio)quinazolinedihydrochloride), TNFERADE™ (adenovector: DNA carrier containing thegene for tumor necrosis factor-α), TRACLEER® or ZAVESCA® (bosentan),tretinoin (Retin-A), tetrandrine, TRISENOX® (arsenic trioxide),VIRULIZIN®, ukrain (derivative of alkaloids from the greater celandineplant), vitaxin (anti-alphavbeta3 antibody), XCYTRIN® (motexafingadolinium), XINLAY™ (atrasentan), XYOTAX™ (paclitaxel poliglumex),YONDELIS® (trabectedin), ZD-6126, ZINECARD® (dexrazoxane), ZOMETA®(zolendronic acid), zorubicin and the like.

The compounds of the invention can also be co-administered with atherapeutically effective amount of one or more agents to treat aninflammatory disease or condition, or autoimmune disease, where examplesof the agents include, such as methotrexate, 6-mercaptopurine,azathioprine sulphasalazine, mesalazine, olsalazinechloroquinine/hydroxychloroquine, pencillamine, aurothiomalate(intramuscular and oral), azathioprine, cochicine, corticosteroids(oral, inhaled and local injection), beta-2 adrenoreceptor agonists(salbutamol, terbutaline, salmeteral), xanthines (theophylline,aminophylline), cromoglycate, nedocromil, ketotifen, ipratropium andoxitropium, cyclosporin, FK506, rapamycin, mycophenolate mofetil,leflunomide, NSAIDs, for example, ibuprofen, corticosteroids such asprednisolone, phosphodiesterase inhibitors, adensosine agonists,antithrombotic agents, complement inhibitors, adrenergic agents, agentswhich interfere with signalling by proinflammatory cytokines such asTNFα or IL-1 (e.g., NIK, IKK, p38 or MAP kinase inhibitors), IL-1βconverting enzyme inhibitors, T-cell signalling inhibitors such askinase inhibitors, metalloproteinase inhibitors, sulfasalazine,6-mercaptopurines, angiotensin converting enzyme inhibitors, solublecytokine receptors and derivatives thereof (e.g. soluble p55 or p75 TNFreceptors and the derivatives p75TNFRIgG (etanercept) and p55TNFRIgG(Lenercept), sIL-1RI, sIL-1RII, sIL-6R), antiinflammatory cytokines(e.g. IL-4, IL-10, IL-11, IL-13 and TGFβ), celecoxib, folic acid,hydroxychloroquine sulfate, rofecoxib, etanercept, infliximab, naproxen,valdecoxib, sulfasalazine, methylprednisolone, meloxicam,methylprednisolone acetate, gold sodium thiomalate, aspirin,triamcinolone acetonide, propoxyphene napsylate/apap, folate,nabumetone, diclofenac, piroxicam, etodolac, diclofenac sodium,oxaprozin, oxycodone HCl, hydrocodone bitartrate/apap, diclofenacsodium/misoprostol, fentanyl, anakinra, tramadol HCl, salsalate,sulindac, cyanocobalamin/fa/pyridoxine, acetaminophen, alendronatesodium, prednisolone, morphine sulfate, lidocaine hydrochloride,indomethacin, glucosamine sulf/chondroitin, amitriptyline HCl,sulfadiazine, oxycodone HCl/acetaminophen, olopatadine HCl misoprostol,naproxen sodium, omeprazole, cyclophosphamide, rituximab, IL-1 TRAP,MRA, CTLA4-IG, IL-18 BP, anti-IL-12, Anti-IL15, BIRB-796, SCIO-469,VX-702, AMG-548, VX-740, Roflumilast, IC-485, CDC-801, S1P1 agonists(such as FTY720), PKC family inhibitors (such as Ruboxistaurin orAEB-071) and Mesopram. In certain embodiments, combinations includemethotrexate or leflunomide and in moderate or severe rheumatoidarthritis cases, cyclosporine and anti-TNF antibodies as noted above.

Non-limiting examples of therapeutic agents for inflammatory boweldisease with which a compound of formula (I) of the invention may beco-administered include the following: budenoside; epidermal growthfactor; corticosteroids; cyclosporin, sulfasalazine; aminosalicylates;6-mercaptopurine; azathioprine; metronidazole; lipoxygenase inhibitors;mesalamine; olsalazine; balsalazide; antioxidants; thromboxaneinhibitors; IL-1 receptor antagonists; anti-IL-1β monoclonal antibodies;anti-IL-6 monoclonal antibodies; growth factors; elastase inhibitors;pyridinyl-imidazole compounds; antibodies to or antagonists of otherhuman cytokines or growth factors, for example, TNF, LT, IL-1, IL-2,IL-6, IL-7, IL-8, IL-12, IL-15, IL-16, IL-23, EMAP-II, GM-CSF, FGF, andPDGF; cell surface molecules such as CD2, CD3, CD4, CD8, CD25, CD28,CD30, CD40, CD45, CD69, CD90 or their ligands; methotrexate;cyclosporine; FK506; rapamycin; mycophenolate mofetil; leflunomide;NSAIDs, for example, ibuprofen; corticosteroids such as prednisolone;phosphodiesterase inhibitors; adenosine agonists; antithrombotic agents;complement inhibitors; adrenergic agents; agents which interfere withsignalling by proinflammatory cytokines such as TNFα or IL-1 (e.g. NIK,IKK, or MAP kinase inhibitors); IL-1β converting enzyme inhibitors; TNFαconverting enzyme inhibitors; T-cell signalling inhibitors such askinase inhibitors; metalloproteinase inhibitors; sulfasalazine;azathioprine; 6-mercaptopurines; angiotensin converting enzymeinhibitors; soluble cytokine receptors and derivatives thereof (e.g.soluble p55 or p75 TNF receptors, sIL-1RI, sIL-1RII, sIL-6R) andantiinflammatory cytokines (e.g. IL-4, IL-10, IL-11, IL-13 and TGFβ).Preferred examples of therapeutic agents for Crohn's disease with whicha compound of formula (I) may be combined include the following: TNFantagonists, for example, anti-TNF antibodies, D2E7 (adalimumab), CA2(infliximab), CDP 571, TNFR-Ig constructs, (p75TNFRIgG (etanercept) andp55TNFRIgG (LENERCEPT™) inhibitors and PDE4 inhibitors. A compound offormula (I) may be combined with corticosteroids, for example,budenoside and dexamethasone; sulfasalazine, 5-aminosalicylic acid;olsalazine; and agents which interfere with synthesis or action ofproinflammatory cytokines such as IL-1, for example, IL-1β convertingenzyme inhibitors and IL-1ra; T cell signaling inhibitors, for example,tyrosine kinase inhibitors; 6-mercaptopurine; IL-11; mesalamine;prednisone; azathioprine; mercaptopurine; infliximab; methylprednisolonesodium succinate; diphenoxylate/atrop sulfate; loperamide hydrochloride;methotrexate; omeprazole; folate; ciprofloxacin/dextrose-water;hydrocodone bitartrate/apap; tetracycline hydrochloride; fluocinonide;metronidazole; thimerosal/boric acid; cholestyramine/sucrose;ciprofloxacin hydrochloride; hyoscyamine sulfate; meperidinehydrochloride; midazolam hydrochloride; oxycodone HCl/acetaminophen;promethazine hydrochloride; sodium phosphate;sulfamethoxazole/trimethoprim; celecoxib; polycarbophil; propoxyphenenapsylate; hydrocortisone; multivitamins; balsalazide disodium; codeinephosphate/apap; colesevelam HCl; cyanocobalamin; folic acid;levofloxacin; methylprednisolone; natalizumab and interferon-gamma.

Non-limiting examples of therapeutic agents for multiple sclerosis withwhich a compound of formula (I) may be co-administered include thefollowing: corticosteroids; prednisolone; methylprednisolone;azathioprine; cyclophosphamide; cyclosporine; methotrexate;4-aminopyridine; tizanidine; interferon-β1a (AVONEX®; Biogen);interferon-β1b (BETASERON®; Chiron/Berlex); interferon α-n3) (InterferonSciences/Fujimoto), interferon-α (Alfa Wassermann/J&J), interferonβ1A-IF (Serono/Inhale Therapeutics), Peginterferon α 2b(Enzon/Schering-Plough), Copolymer 1 (Cop-1; COPAXONE®; TevaPharmaceutical Industries, Inc.); hyperbaric oxygen; intravenousimmunoglobulin; cladribine; antibodies to or antagonists of other humancytokines or growth factors and their receptors, for example, TNF, LT,IL-1, IL-2, IL-6, IL-7, IL-8, IL-12, IL-23, IL-15, IL-16, EMAP-II,GM-CSF, FGF, and PDGF. A compound of formula (I) may be combined withantibodies to cell surface molecules such as CD2, CD3, CD4, CD8, CD19,CD20, CD25, CD28, CD30, CD40, CD45, CD69, CD80, CD86, CD90 or theirligands. A compound of formula (I) may also be combined with agents suchas methotrexate, cyclosporine, FK506, rapamycin, mycophenolate mofetil,leflunomide, an S1P1 agonist, NSAIDs, for example, ibuprofen,corticosteroids such as prednisolone, phosphodiesterase inhibitors,adensosine agonists, antithrombotic agents, complement inhibitors,adrenergic agents, agents which interfere with signalling byproinflammatory cytokines such as TNFα or IL-1 (e.g., NIK, IKK, p38 orMAP kinase inhibitors), IL-1β converting enzyme inhibitors, TACEinhibitors, T-cell signaling inhibitors such as kinase inhibitors,metalloproteinase inhibitors, sulfasalazine, azathioprine,6-mercaptopurines, angiotensin converting enzyme inhibitors, solublecytokine receptors and derivatives thereof (e.g. soluble p55 or p75 TNFreceptors, sIL-1RI, sIL-1RII, sIL-6R) and antiinflammatory cytokines(e.g. IL-4, IL-10, IL-13 and TGFβ).

A compound of formula (I) may also be co-administered with agents, suchas alemtuzumab, dronabinol, daclizumab, mitoxantrone, xaliprodenhydrochloride, fampridine, glatiramer acetate, natalizumab, sinnabidol,α-immunokine NNSO3, ABR-215062, AnergiX.MS, chemokine receptorantagonists, BBR-2778, calagualine, CPI-1189, LEM (liposome encapsulatedmitoxantrone), THC.CBD (cannabinoid agonist), MBP-8298, mesopram (PDE4inhibitor), MNA-715, anti-IL-6 receptor antibody, neurovax, pirfenidoneallotrap 1258 (RDP-1258), sTNF-R1, talampanel, teriflunomide, TGF-beta2,tiplimotide, VLA-4 antagonists (for example, TR-14035, VLA4 Ultrahaler,Antegran-ELAN/Biogen), interferon gamma antagonists and IL-4 agonists.

Non-limiting examples of therapeutic agents for ankylosing spondylitiswith which a compound of formula (I) may be co-administered include thefollowing: ibuprofen, diclofenac, misoprostol, naproxen, meloxicam,indomethacin, diclofenac, celecoxib, rofecoxib, sulfasalazine,methotrexate, azathioprine, minocyclin, prednisone, and anti-TNFantibodies, D2E7 (HUMIRA®), CA2 (infliximab), CDP 571, TNFR-Igconstructs, (p75TNFRIgG (ENBREL®) and p55TNFRIgG (LENERCEPT®).

Non-limiting examples of therapeutic agents for asthma with which acompound of formula (I) may be co-administered include the following:albuterol, salmeterol/fluticasone, montelukast sodium, fluticasonepropionate, budesonide, prednisone, salmeterol xinafoate, levalbuterolHCl, albuterol sulfate/ipratropium, prednisolone sodium phosphate,triamcinolone acetonide, beclomethasone dipropionate, ipratropiumbromide, azithromycin, pirbuterol acetate, prednisolone, theophyllineanhydrous, methylprednisolone sodium succinate, clarithromycin,zafirlukast, formoterol fumarate, influenza virus vaccine, amoxicillintrihydrate, flunisolide, allergy injection, cromolyn sodium,fexofenadine hydrochloride, flunisolide/menthol,amoxicillin/clavulanate, levofloxacin, inhaler assist device,guaifenesin, dexamethasone sodium phosphate, moxifloxacin HCl,doxycycline hyclate, guaifenesin/d-methorphan,p-ephedrine/cod/chlorphenir, gatifloxacin, cetirizine hydrochloride,mometasone furoate, salmeterol xinafoate, benzonatate, cephalexin,pe/hydrocodone/chlorphenir, cetirizine HCl/pseudoephed,phenylephrine/cod/promethazine, codeine/promethazine, cefprozil,dexamethasone, guaifenesin/pseudoephedrine,chlorpheniramine/hydrocodone, nedocromil sodium, terbutaline sulfate,epinephrine, methylprednisolone, anti-IL-13 antibody, and metaproterenolsulfate.

Non-limiting examples of therapeutic agents for COPD with which acompound of formula (I) may be co-administered include the following:albuterol sulfate/ipratropium, ipratropium bromide,salmeterol/fluticasone, albuterol, salmeterol xinafoate, fluticasonepropionate, prednisone, theophylline anhydrous, methylprednisolonesodium succinate, montelukast sodium, budesonide, formoterol fumarate,triamcinolone acetonide, levofloxacin, guaifenesin, azithromycin,beclomethasone dipropionate, levalbuterol HCl, flunisolide, ceftriaxonesodium, amoxicillin trihydrate, gatifloxacin, zafirlukast,amoxicillin/clavulanate, flunisolide/menthol,chlorpheniramine/hydrocodone, metaproterenol sulfate,methylprednisolone, mometasone furoate, p-ephedrine/cod/chlorphenir,pirbuterol acetate, p-ephedrine/loratadine, terbutaline sulfate,tiotropium bromide, (R,R)-formoterol, TgAAT, cilomilast and roflumilast.

Non-limiting examples of therapeutic agents for psoriasis with which acompound of formula (I) may be co-administered include the following:calcipotriene, clobetasol propionate, triamcinolone acetonide,halobetasol propionate, tazarotene, methotrexate, fluocinonide,betamethasone diprop augmented, fluocinolone acetonide, acitretin, tarshampoo, betamethasone valerate, mometasone furoate, ketoconazole,pramoxine/fluocinolone, hydrocortisone valerate, flurandrenolide, urea,betamethasone, clobetasol propionate/emoll, fluticasone propionate,azithromycin, hydrocortisone, moisturizing formula, folic acid,desonide, pimecrolimus, coal tar, diflorasone diacetate, etanerceptfolate, lactic acid, methoxsalen, hc/bismuth subgal/znox/resor,methylprednisolone acetate, prednisone, sunscreen, halcinonide,salicylic acid, anthralin, clocortolone pivalate, coal extract, coaltar/salicylic acid, coal tar/salicylic acid/sulfur, desoximetasone,diazepam, emollient, fluocinonide/emollient, mineral oil/castor oil/nalact, mineral oil/peanut oil, petroleum/isopropyl myristate, psoralen,salicylic acid, soap/tribromsalan, thimerosal/boric acid, celecoxib,infliximab, cyclosporine, alefacept, efalizumab, tacrolimus,pimecrolimus, PUVA, UVB, sulfasalazine, ABT-874 and ustekinamab.

Non-limiting examples of therapeutic agents for psoriatic arthritis withwhich a compound of formula (I) may be co-administered include thefollowing: methotrexate, etanercept, rofecoxib, celecoxib, folic acid,sulfasalazine, naproxen, leflunomide, methylprednisolone acetate,indomethacin, hydroxychloroquine sulfate, prednisone, sulindac,betamethasone diprop augmented, infliximab, methotrexate, folate,triamcinolone acetonide, diclofenac, dimethylsulfoxide, piroxicam,diclofenac sodium, ketoprofen, meloxicam, methylprednisolone,nabumetone, tolmetin sodium, calcipotriene, cyclosporine, diclofenacsodium/misoprostol, fluocinonide, glucosamine sulfate, gold sodiumthiomalate, hydrocodone bitartrate/apap, ibuprofen, risedronate sodium,sulfadiazine, thioguanine, valdecoxib, alefacept, D2E7 (adalimumab), andefalizumab.

Preferred examples of therapeutic agents for SLE (Lupus) with which acompound of formula (I) may be co-administered include the following:NSAIDS, for example, diclofenac, naproxen, ibuprofen, piroxicam,indomethacin; COX2 inhibitors, for example, celecoxib, rofecoxib,valdecoxib; anti-malarials, for example, hydroxychloroquine; steroids,for example, prednisone, prednisolone, budenoside, dexamethasone;cytotoxics, for example, azathioprine, cyclophosphamide, mycophenolatemofetil, methotrexate; inhibitors of PDE4 or purine synthesis inhibitor,for example Cellcept®. A compound of formula (I) may also be combinedwith agents such as sulfasalazine, 5-aminosalicylic acid, olsalazine,Imuran® and agents which interfere with synthesis, production or actionof proinflammatory cytokines such as IL-1, for example, caspaseinhibitors like IL-13 converting enzyme inhibitors and IL-1ra. Acompound of formula (I) may also be used with T cell signalinginhibitors, for example, tyrosine kinase inhibitors; or molecules thattarget T cell activation molecules, for example, CTLA-4-IgG or anti-B7family antibodies, anti-PD-1 family antibodies. A compound of formula(I) may be combined with IL-11 or anti-cytokine antibodies, for example,fonotolizumab (anti-IFNg antibody), or anti-receptor receptorantibodies, for example, anti-IL-6 receptor antibody and antibodies toB-cell surface molecules. A compound of formula (I) may also be usedwith LJP 394 (abetimus), agents that deplete or inactivate B-cells, forexample, Rituximab (anti-CD20 antibody), lymphostat-B (anti-BlySantibody), TNF antagonists, for example, anti-TNF antibodies, D2E7(adalimumab), CA2 (infliximab), CDP 571, TNFR-Ig constructs, (p75TNFRIgG(etanercept) and p55TNFRIgG (LENERCEPT™).

The compounds of the invention can also be co-administered with atherapeutically effective amount of one or more agents used in theprevention or treatment of AIDS, where examples of the agents include,HIV reverse transcriptase inhibitors, HIV protease inhibitors,immunomodulators, and other retroviral drugs. Examples of reversetranscriptase inhibitors include, but are not limited to, abacavir,adefovir, didanosine, dipivoxil delavirdine, efavirenz, lamivudine,nevirapine, stavudine zalcitabine, and zidovudine. Examples of proteaseinhibitors include, but are not limited to, amprenavir, indinavir,lopinavir, nelfinavir, ritonavir, and saquinavir.

The following Examples may be used for illustrative purposes and shouldnot be deemed to narrow the scope of the invention.

EXAMPLES Example 14-[2-(cyclopropylmethoxy)-4-(3-methyl-1H-pyrazol-5-yl)phenyl]-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-oneExample 1a

(E)-2-(5-bromo-2-methoxy-3-nitropyridin-4-yl)-N,N-dimethylethenamine5-Bromo-2-methoxy-4-methyl-3-nitropyridine (15.0 g, 60.7 mmol) wasdissolved in dimethylformamide (300 mL), and lithium methanolate (6.07mL, 6.07 mmol, 1 M) was added. The reaction mixture was heated at 100°C. To this mixture was added 1,1-dimethoxy-N,N-dimethylmethanamine (64.5mL, 486 mmol) over 10 minutes. The reaction mixture was stirred at 95°C. for 16 hours. The reaction mixture was cooled to ambient temperatureand water was added carefully (300 mL, exothermic). The resultingprecipitate was collected by vacuum filtration, washed with water, anddried to provide the title compound (13.9 g, 45.9 mmol, 76% yield).

Example 1b 4-bromo-7-methoxy-1H-pyrrolo[2,3-c]pyridine

Example 1a (13.9 g, 45.8 mmol) and ethyl acetate (150 mL) were added toRa-Ni 2800 (pre-washed with ethanol), water slurry (6.9 g, 118 mmol) ina stainless steel pressure bottle and stirred for 30 minutes at 30 psiof H₂ and ambient temperature. The reaction mixture was filtered, andconcentrated. The residue was triturated with dichloromethane, and thesolid filtered to provide the title compound (5.82 g). The mother liquorwas concentrated and the residue triturated again with dichloromethaneand filtered to provide an additional 1.63 g of the title compound.Total yield=7.45 g, 72% yield

Example 1c 4-bromo-7-methoxy-1-tosyl-1H-pyrrolo[2,3-c]pyridine

A solution of Example 1b (7.42 g, 32.7 mmol) in dimethylformamide (235mL) was stirred at ambient temperature. To this solution was addedsodium hydride (1.18 g, 1.96 g of 60% dispersion in oil, 49.0 mmol), andthe reaction mixture was stirred for 10 minutes. P-toluenesulfonylchloride (9.35 g, 49.0 mmol) was then added portion-wise, and themixture was stirred at ambient temperature under nitrogen for 16 hours.The reaction mixture was quenched carefully with water and the resultingbeige solid collected by vacuum filtration on a Buchner funnel, andwashed with water. The solid was collected and dried in a vacuum oven at50° C. to provide 12.4 g (100%) of the title compound.

Example 1d 4-bromo-1-tosyl-1H-pyrrolo[2,3-c]pyridin-7(6H)-one

A solution of Example 1c (12.4 g, 32.6 mmol) in dioxane (140 mL) wasstirred at ambient temperature. To this solution was added 4M HCl indioxane (140 mL). The reaction mixture was stirred at 40° C. for 16hours. The reaction mixture was cooled to ambient temperature andconcentrated. The residue was triturated with diethylether, filtered,and rinsed with additional diethylether and dried to provide the titlecompound (11.23 g, 30.6 mmol, 94% yield) as a beige solid.

Example 1e 4-bromo-6-methyl-1-tosyl-1H-pyrrolo[2,3-c]pyridin-7(6H)-one

Sodium hydride (0.875 g, 36.5 mmol, 1.46 g of a 60% in oil dispersion)was added to a stirring solution of Example 1d (11.2 g, 30.4 mmol) indimethylformamide (217 mL) under nitrogen. After 30 minutes, iodomethane(2.27 mL, 36.5 mmol) was added and the solution was stirred at ambienttemperature for 3 hours. Upon addition of water (250 mL) a precipitateformed. The precipitate was collected by vacuum filtration, rinsed withwater (50 mL) and dried in a vacuum oven at 55° C. overnight to provide11.2 g of the title compound (96%).

Example 1f6-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-tosyl-1H-pyrrolo[2,3-c]pyridin-7(6H)-one

Example 1e (6.55 g, 17.2 mmol),4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (8.73 g,34.4 mmol), potassium acetate (3.71 g, 37.8 mmol),tris(dibenzylideneacetone)dipalladium(0) (0.393 g, 0.430 mmol) and2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl (X-PHOS, 0.819 g,1.72 mmol) were combined and sparged with argon for 1 hour withstirring. Dioxane (86 mL) was sparged with nitrogen for 1 hour, andtransferred via cannula under nitrogen to the solid components. Themixture was heated under argon at 80° C. for 5 hours. The reactionmixture was cooled to ambient temperature, partitioned between ethylacetate and water, and filtered through Celite. The ethyl acetate layerwas washed twice with saturated aqueous sodium chloride, dried(anhydrous sodium sulfate), filtered, and concentrated. The residue waspurified by chromatography (silica gel, 25-80% ethyl acetate in hexane).The resulting material from chromatography was triturated with a minimalamount of hexanes (30 mL) and the particulate solid was collected byfiltration, rinsed with a minimal amount of hexanes and dried toconstant mass to afford the title compound (5.4 g, 73%).

Example 1g 1-(4-bromo-3-(cyclopropylmethoxy)phenyl)ethanone

1-(4-bromo-3-hydroxyphenyl)ethanone (2.04 g, 9.50 mmol),(bromomethyl)cyclopropane (1.01 mL, 10.5 mmol) and potassium carbonate(1.58 g, 11.4 mmol) were combined in dimethylsulfoxide (10 mL). Thereaction mixture was heated at 50° C. for 3 hours. The reaction mixturewas partitioned with ethyl acetate and water. The organic layer waswashed with saturated aqueous sodium chloride, dried with anhydroussodium sulfate, filtered, and concentrated. The residue was purified byflash chromatography (silica gel, 10-20% ethyl acetate in heptanes) toprovide the title compound (2.05 g, 80%).

Example 1h(Z)-1-(4-bromo-3-(cyclopropylmethoxy)phenyl)-3-hydroxybut-2-en-1-one

Example 1g (1.66 g, 6.17 mmol), sodium ethoxide (0.504 g, 7.40 mmol) andanhydrous ethyl acetate (2.42 mL, 24.7 mmol) were combined and stirredat ambient temperature for 18 hours. To this reaction mixture was addedsodium ethoxide (0.840 mg, 1.23 mmol) again and the mixture was stirredat ambient temperature for an additional 4 hours. The reaction mixturewas partitioned with ethyl acetate and 1M HCl. The organic layer waswashed with saturated aqueous sodium chloride, dried with anhydroussodium sulfate, filtered, and concentrated. The residue was purified byflash chromatography (silica gel, 0-10% ethyl acetate in heptanes) toprovide the title compound (1.57 g, 82%).

Example 1i 5-(4-bromo-3-(cyclopropylmethoxy)phenyl)-3-methyl-1H-pyrazole

Example 1h (1.50 g, 4.82 mmol) and hydrazine (0.159 mL, 5.06 mmol) werecombined in ethanol (20 mL). The reaction mixture was stirred at ambienttemperature for 1 hour and concentrated to provide the title compound(1.48 g, 100%).

Example 1j4-[2-(cyclopropylmethoxy)-4-(3-methyl-1H-pyrazol-5-yl)phenyl]-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one

Example 1f (70.0 mg, 0.163 mmol), Example 1i (50.2 mg, 0.163 mmol),cesium fluoride (74.5 mg, 0.490 mmol) andtetrakis(triphenylphosphine)palladium(0) (9.4 mg, 8.1 μmol) werecombined in a mixture of dimethoxyethane (2 mL) and methanol (1 mL). Thereaction mixture was purged with nitrogen for 15 minutes and heated in amicrowave reactor at 130° C. for 80 minutes. The reaction mixture waspartitioned with ethyl acetate and water. The organic layer was washedwith saturated aqueous sodium chloride, dried with anhydrous sodiumsulfate, treated with 3-mercaptopropyl functionalized silica gel,filtered, and concentrated. The residue was purified by flashchromatography (silica gel, 2-6% methanol in dichloromethane) to providethe title compound (34 mg, 56%). ¹H NMR (300 MHz, DMSO-d₆) δ 12.53 (s,1H) 11.93 (s, 1H) 7.08-7.57 (m, 5H) 6.49 (s, 1H) 5.98-6.29 (m, 1H) 3.90(d, J=6.44 Hz, 2H) 3.56 (s, 3H) 2.28 (s, 3H) 1.02-1.15 (m, 1H) 0.41-0.53(m, 2H) 0.18-0.31 (m, 2H). MS (ESI+) m/z 375 (M+H)⁺.

Example 2N-[4-(2,4-difluorophenoxy)-2-[(dimethylamino)methyl]-5-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)phenyl]ethanesulfonamideExample 2a 4-bromo-5-(2,4-difluorophenoxy)-2-nitrobenzoic acid

A mixture of 4-bromo-5-fluoro-2-nitrobenzoic acid (3.5 g, 13.3 mmol),2,4-difluorophenol (1.5 mL, 15.70 mmol), cesium carbonate (9.5 g, 29.2mmol) and dimethylsulfoxide (28 mL) was heated at 110° C. for 1 hour.After cooling to ambient temperature, water (100 mL) was added. Thesolution was acidified with 1N HCl (60 mL) and was extracted with ethylacetate. The ethyl acetate layer was washed with water, saturatedaqueous sodium chloride, dried (anhydrous magnesium sulfate), filtered,and concentrated to provide the title compound (4.73 g, 12.64 mmol, 95%yield)

Example 2b methyl 4-bromo-5-(2,4-difluorophenoxy)-2-nitrobenzoate

Oxalyl dichloride (1.1 mL, 13.00 mmol) was added dropwise to a 0° C.suspension of Example 2a (4.3 g, 11.49 mmol) and dichloromethane (50mL). 3 drops of dimethylformamide were added and the reaction mixturewas stirred at ambient temperature for 2 hours. After cooling to 0° C.,methanol (9.5 mL, 235 mmol) was added dropwise. The solution was stirredfor 15 minutes at 0° C. and for 2.5 hours at ambient temperature Thesolution was diluted with dichloromethane and was washed with water,saturated aqueous sodium bicarbonate solution, dried (anhydrous sodiumsulfate), filtered, and concentrated to provide the title compound (4.3g, 11.08 mmol, 96% yield).

Example 2c methyl 2-amino-4-bromo-5-(2,4-difluorophenoxy)benzoate

A solution of Example 2b (150 mg, 0.386 mmol), iron powder (108 mg,1.934 mmol), ammonia hydrochloride (20.67 mg, 0.386 mmol), ethanol (11mL), tetrahydrofuran (4.4 mL), and water (2.2 mL) was stirred at 85° C.for 3 hours. The reaction mixture was cooled briefly, and filteredthrough Celite. The filter pad was rinsed well with tetrahydrofuran. Thefiltrate was diluted with ethyl acetate and was washed with water,saturated aqueous sodium chloride, dried (anhydrous magnesium sulfate),filtered, and concentrated to provide the title compound (140 mg, 0.391mmol, 101% yield).

Example 2d 4-bromo-5-(2,4-difluorophenoxy)-2-(ethylsulfonamido)benzoicacid

Ethanesulfonyl chloride (3.3 mL, 34.8 mmol) was added dropwise to a 0°C. solution of Example 2c (4.1 g, 11.45 mmol), triethylamine (6.38 mL,45.8 mmol) and dichloromethane (115 mL). The reaction mixture wasstirred at ambient temperature for 18 hours. The reaction mixture wasconcentrated to dryness. To the residue was added 100 mL dioxane and 40mL 10% NaOH. This solution was stirred at 95° C. for 2 hours. Aftercooling to ambient temperature, saturated aqueous NH₄Cl solution wasadded and the solution was extracted with ethyl acetate. The organiclayer was washed with water and saturated aqueous sodium chloridesequentially, dried (anhydrous magnesium sulfate), filtered, andconcentrated to afford 4.5 g of brown foam. The crude product wastriturated with 150 mL hexanes/25 mL Et₂O, filtered and dried (in-vacuo)to provide the title compound (4.3 g, 9.86 mmol, 86% yield).

Example 2eN-(5-bromo-4-(2,4-difluorophenoxy)-2-(hydroxymethyl)phenyl)ethanesulfonamide

Borane tetrahydrofuran complex (1M solution. 20 mL, 20.00 mmol) wasadded to a solution of Example 2d (4.4 g, 10.09 mmol) andtetrahydrofuran (100 mL). The reaction mixture was stirred at reflux for5 hours. After cooling to ambient temperature, methanol (25 mL) wasadded slowly and the solution was concentrated to dryness. 50 mLMethanolic HCl was added to the residue and the solution was stirred atreflux for 45 minutes. After cooling to ambient temperature the solutionwas concentrated to dryness. Toluene (50 mL) and methanol (50 mL) wereadded and then concentrated. The residue was dried (in-vacuo) to afford4.5 g of brown glass. The crude product was absorbed onto silica gel andwas flash chromatographed (Biotage 340 g KP Snap Cartridge, eluting withdichloromethane containing a gradient with methanol, 0% to 5%) toprovide the title compound (3.52 g, 8.34 mmol, 83% yield).

Example 2fN-(5-bromo-4-(2,4-difluorophenoxy)-2-formylphenyl)ethanesulfonamide

Manganese(IV) oxide (1.5 g, 17.25 mmol) was added portionwise to aambient temperature solution of Example 2e (0.566 g, 1.340 mmol) anddichloromethane (23 mL). The reaction mixture was stirred at ambienttemperature for 3 hours. An additional portion of MnO₂ (310 mg, 3.57mmol) was added and the reaction mixture was stirred at ambienttemperature for another 4 hours. The reaction mixture was filteredthrough Celite and the filter pad was washed with tetrahydrofuran. Thecombined filtrate was concentrated to provide the title compound (0.51g, 1.214 mmol, 91% yield).

Example 2gN-(4-(2,4-difluorophenoxy)-2-formyl-5-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)phenyl)ethanesulfonamide

Using the procedure described for Example 1j and substituting Example 2ffor Example 1i provided the title compound.

Example 2hN-[4-(2,4-difluorophenoxy)-2-[(dimethylamino)methyl]-5-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)phenyl]ethanesulfonamide

Dimethylamine (2M solution in methanol, 0.086 mL, 0.172 mmol) was addedto a mixture of Example 2g (150 mg, 0.308 mmol) and 1,2-dichloroethane(1.5 mL). 2 Drops of acetic acid were added (pH 5) and the suspensionwas stirred at ambient temperature for 2 hours. Sodiumtriacetoxyhydroborate (65 mg, 0.308 mmol) was added portionwise and thereaction mixture was stirred at ambient temperature for 24 hours. Thereaction mixture was diluted with dichloromethane and was washed withsaturated aqueous sodium bicarbonate solution and saturated aqueoussodium chloride sequentially, dried (anhydrous sodium sulfate),filtered, and concentrated to afford 130 mg orange foam. The crudeproduct was purified by preparative HPLC on a Phenomenex Luna C8(2) 5 μm100 Å AXIA column (30 mm×75 mm). A gradient of acetonitrile (A) and 10mM ammonium acetate in water (B) was used, at a flow rate of 50mL/minutes (0-0.5 minutes 10% A, 0.5-7.0 minutes linear gradient 10-95%A, 7.0-10.0 minutes 95% A, 10.0-12.0 minutes linear gradient 95-10% A).Samples were injected in 1.5 mL DMSO:methanol (1:1). A custompurification system was used, consisting of the following modules:Waters LC4000 preparative pump; Waters 996 diode-array detector; Waters717+ autosampler; Waters SAT/IN module, Alltech Varex III evaporativelight-scattering detector; Gilson 506C interface box; and two GilsonFC204 fraction collectors. The system was controlled using WatersMillennium32 software, automated using an Abbott developed Visual Basicapplication for fraction collector control and fraction tracking.Fractions were collected based upon UV signal threshold and selectedfractions subsequently analyzed by flow injection analysis massspectrometry using positive APCI ionization on a Finnigan LCQ using70:30 methanol: 10 mM NH₄OH(aq) at a flow rate of 0.8 mL/minutes.Loop-injection mass spectra were acquired using a Finnigan LCQ runningLCQ Navigator 1.2 software and a Gilson 215 liquid handler for fractioninjection controlled by an Abbott developed Visual Basic application.Purification as described provided the title compound (34 mg, 0.066mmol, 21% yield). ¹H NMR (300 MHz, DMSO-d₆) δ 12.03 (s, 1H), 7.49 (s,1H), 7.42-7.30 (m, 2H), 7.28 (t, J=2.7 Hz, 1H), 7.15-7.04 (m, 1H), 7.00(ddd, J=10.7, 6.1, 2.1 Hz, 1H), 6.87 (s, 1H), 6.30-6.21 (m, 1H), 3.54(d, J=8.7 Hz, 6H), 3.21 (dd, J=14.7, 7.3 Hz, 2H), 2.20 (s, 6H), 1.25 (t,J=7.3 Hz, 3H). MS (ESI+) m/z 516.9 (M+H)⁺.

Example 3N-[4-(2,4-difluorophenoxy)-5-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-2-(piperidin-1-ylmethyl)phenyl]ethanesulfonamide

Example 3 was prepared according to the procedure used for thepreparation of Example 2h, substituting piperidine for dimethylamine andwas purified by preparative HPLC on a Phenomenex Luna C8(2) 5 μm 100 ÅAXIA column (30 mm×75 mm). A gradient of acetonitrile (A) and 0.1%trifluoroacetic acid in water (B) was used, at a flow rate of 50 mL/min(0-0.5 min 10% A, 0.5-7.0 min linear gradient 10-95% A, 7.0-10.0 min 95%A, 10.0-12.0 min linear gradient 95-10% A). Samples were injected in 1.5mL DMSO:methanol (1:1). A custom purification system was used,consisting of the following modules: Waters LC4000 preparative pump;Waters 996 diode-array detector; Waters 717+ autosampler; Waters SAT/INmodule, Alltech Varex III evaporative light-scattering detector; Gilson506C interface box; and two Gilson FC204 fraction collectors. The systemwas controlled using Waters Millennium32 software, automated using anAbbott developed Visual Basic application for fraction collector controland fraction tracking. Fractions were collected based upon UV signalthreshold and selected fractions subsequently analyzed by flow injectionanalysis mass spectrometry using positive APCI ionization on a FinniganLCQ using 70:30 MeOH:10 mM NH₄OH(aq) at a flow rate of 0.8 mL/min.Loop-injection mass spectra were acquired using a Finnigan LCQ runningLCQ Navigator 1.2 software and a Gilson 215 liquid handler for fractioninjection controlled by an Abbott developed Visual Basic application. toprovide the TFA salt of the title compound. ¹H NMR (300 MHz, DMSO-d₆) δ12.10 (s, 1H), 9.40 (s, 1H), 8.98 (s, 1H), 7.51 (s, 1H), 7.44 (ddd,J=11.5, 8.8, 3.0 Hz, 1H), 7.35 (s, 1H), 7.31 (t, J=2.8 Hz, 1H),7.28-7.19 (m, 2H), 7.07 (dd, J=11.8, 5.4 Hz, 1H), 6.30 (dd, J=2.6, 2.1Hz, 1H), 4.41 (d, J=5.3 Hz, 2H), 3.55 (s, 3H), 3.30 (s, 2H), 3.21 (q,J=7.3 Hz, 2H), 2.95 (d, J=11.6 Hz, 2H), 1.83 (d, J=14.5 Hz, 2H),1.75-1.51 (m, 3H), 1.41 (d, J=11.5 Hz, 1H), 1.28 (t, J=7.3 Hz, 3H). MS(ESI+) m/z 557.0 [M+H]⁺.

Example 4N-[4-(2,4-difluorophenoxy)-5-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-2-(morpholin-4-ylmethyl)phenyl]ethanesulfonamide

Example 4 was prepared according to the procedure used for thepreparation of Example 2h, substituting morpholine for dimethylamine andwas purified according to the procedure described in Example 3 toprovide the TFA salt of the title compound. ¹H NMR (500 MHz, DMSO-d₆) δ12.09 (s, 1H), 9.58 (d, J=150.2 Hz, 1H), 7.53 (s, 1H), 7.42 (ddd,J=11.5, 8.8, 3.0 Hz, 1H), 7.34 (s, 1H), 7.30 (t, J=2.8 Hz, 1H), 7.21(td, J=9.4, 5.8 Hz, 2H), 7.08-7.00 (m, 1H), 6.29 (t, J=2.4 Hz, 1H), 4.41(s, 2H), 3.93 (s, 3H), 3.42 (dd, J=13.6, 10.2 Hz, 3H), 3.21 (q, J=7.3Hz, 3H), 3.18-3.01 (m, 2H), 1.27 (t, J=7.3 Hz, 3H), 0.43-0.42 (m, 1H),0.41-0.40 (m, 1H). MS (ESI+) m/z 559.0 (M+H)⁺.

Example 5N-{4-(2,4-difluorophenoxy)-5-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-2-[(4-methylpiperazin-1-yl)methyl]phenyl}ethanesulfonamide

Example 5 was prepared according to the procedure used for thepreparation of Example 2h, substituting 4-methylpiperazine fordimethylamine, and purified according to the procedure described inExample 3, to provide the title compound to provide the TFA salt of thetitle compound. ¹H NMR (400 MHz, DMSO-d₆) δ 12.04 (s, 1H), 9.20 (s, 2H),7.46 (s, 1H), 7.38 (ddd, J=11.5, 8.8, 3.0 Hz, 1H), 7.28 (dd, J=5.1, 2.1Hz, 2H), 7.10 (td, J=9.2, 5.6 Hz, 1H), 7.04-6.92 (m, 2H), 6.33-6.22 (m,1H), 3.70 (d, J=14.3 Hz, 2H), 3.52 (s, 3H), 3.40 (s, 2H), 3.20 (q, J=7.3Hz, 2H), 2.94 (s, 4H), 2.79 (s, 3H), 2.37 (s, 2H), 1.26 (t, J=7.3 Hz,3H). MS (ESI+) m/z 572.0 (M+H)⁺.

Example 6N-[4-(2,4-difluorophenoxy)-2-(hydroxymethyl)-5-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)phenyl]ethanesulfonamide

Example 6 was prepared according to the procedure used for thepreparation of Example 1j, substituting Example 2e for Example 1i. ¹HNMR (300 MHz, DMSO-d₆) δ 12.07 (s, 1H), 9.05 (s, 1H), 7.44 (ddd, J=11.5,8.8, 3.0 Hz, 1H), 7.35 (s, 1H), 7.33 (s, 1H), 7.29 (t, J=2.8 Hz, 1H),7.21 (td, J=9.2, 5.7 Hz, 1H), 7.07 (tdd, J=9.3, 3.0, 1.5 Hz, 1H), 6.94(s, 1H), 6.32-6.24 (m, 1H), 5.32 (s, 1H), 4.60 (s, 2H), 3.55 (s, 3H),3.18-3.05 (m, 2H), 1.34-1.15 (m, 3H). MS (ESI+) m/z 490.1 (M+H)⁺.

Example 7N-{2-[(cyclopentylamino)methyl]-4-(2,4-difluorophenoxy)-5-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)phenyl}ethanesulfonamide

Example 7 was prepared according to the procedure used for thepreparation of Example 2h, substituting cyclopentanamine fordimethylamine. ¹H NMR (300 MHz, DMSO-d₆) δ 12.11 (s, 1H), 9.41 (s, 1H),8.61 (s, 2H), 7.52-7.40 (m, 2H), 7.32 (dd, J=6.1, 3.4 Hz, 2H), 7.25-7.13(m, 2H), 7.09 (dd, J=12.4, 6.1 Hz, 1H), 6.25 (t, J=2.3 Hz, 1H), 4.25 (s,2H), 3.55 (s, 3H), 3.20 (q, J=7.3 Hz, 3H), 1.98 (d, J=8.4 Hz, 2H),1.77-1.42 (m, 6H), 1.37-1.21 (m, 3H). MS (ESI+) m/z 556.9 (M+H)⁺.

Example 85-(2,4-difluorophenoxy)-2-[(ethylsulfonyl)amino]-4-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)benzamideExample 8a 4-bromo-5-(2,4-difluorophenoxy)-2-(ethylsulfonamido)benzamide

Oxalyl dichloride (0.046 mL, 0.544 mmol) was added dropwise to asuspension of Example 2d (214 mg, 0.491 mmol) and dichloromethane (2.2mL). 1 Drop of dimethylformamide was added and the reaction mixture wasstirred at ambient temperature for 2 hours. Solvent was evaporated andthe residue was dried (in-vacuo). The acid chloride was suspended intetrahydrofuran (1.0 mL) and was cooled to 0° C. as ammonium hydroxide(0.65 mL, 4.67 mmol) was added dropwise. The reaction mixture wasstirred at ambient temperature for 2 hours. The reaction mixture wasdiluted with ethyl acetate and was washed with water, saturated aqueoussodium chloride, dried (anhydrous magnesium sulfate), filtered, andconcentrated to afford 150 mg brown oil. The crude product was absorbedonto silica gel and was flash chromatographed (Biotage 25 g HP SnapCartridge, eluting with dichloromethane, containing a gradient withmethanol, 1% to 8%) to provide the title compound (0.76 g, 0.404 mmol,82% yield).

Example 8b5-(2,4-difluorophenoxy)-2-[(ethylsulfonyl)amino]-4-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)benzamide

Using the procedure described for Example 1j and substituting Example 8afor Example 1i provided the title compound. ¹H NMR (300 MHz, DMSO-d₆) δ12.12 (s, 1H), 11.60 (s, 1H), 8.46 (s, 1H), 7.96 (s, 1H), 7.74 (s, 1H),7.60 (s, 1H), 7.43-7.38 (m, 1H), 7.38-7.28 (m, 2H), 7.08-7.00 (m, 1H),7.00-6.90 (m, 1H), 6.52-6.03 (m, 1H), 3.53 (s, 3H), 3.30-3.17 (m, 2H),1.20 (t, J=7.3 Hz, 3H). MS (ESI+) m/z 503.1 (M+H)⁺.

Example 9N-cyclopentyl-5-(2,4-difluorophenoxy)-2-[(ethylsulfonyl)amino]-4-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)benzamideExample 9a

4-bromo-N-cyclopentyl-5-(2,4-difluorophenoxy)-2-(ethylsulfonamido)benzamideN1-((ethylimino)methylene)-N3,N3-dimethylpropane-1,3-diaminehydrochloride (95 mg, 0.496 mmol) and N-ethyl-N-isopropylpropan-2-amine(180 μL, 1.031 mmol) were added to a solution of Example 2d (180 mg,0.413 mmol), cyclopentanamine (41 μL, 0.415 mmol),1H-benzo[d][1,2,3]triazol-1-ol hydrate (75 mg, 0.490 mmol) anddimethylformamide (4 mL). The reaction mixture was stirred for 18 hoursat ambient temperature Solvent was evaporated and the residue wasdissolved in dichloromethane, washed with water, saturated aqueoussodium chloride, dried (anhydrous magnesium sulfate), filtered, andconcentrated to afford 210 mg brown foam. The crude product was purifiedby preparative HPLC on a Phenomenex Luna C8(2) 5 μm 100 Å AXIA column(30 mm×75 mm). A gradient of acetonitrile (A) and 0.1% trifluoroaceticacid in water (B) was used, at a flow rate of 50 mL/minutes (0-0.5minutes 10% A, 0.5-7.0 minutes linear gradient 10-95% A, 7.0-10.0minutes 95% A, 10.0-12.0 minutes linear gradient 95-10% A). Samples wereinjected in 1.5 mL DMSO:methanol (1:1). A custom purification system wasused, consisting of the following modules: Waters LC4000 preparativepump; Waters 996 diode-array detector; Waters 717+ autosampler; WatersSAT/IN module, Alltech Varex III evaporative light-scattering detector;Gilson 506C interface box; and two Gilson FC204 fraction collectors. Thesystem was controlled using Waters Millennium32 software, automatedusing an Abbott developed Visual Basic application for fractioncollector control and fraction tracking. Fractions were collected basedupon UV signal threshold and selected fractions subsequently analyzed byflow injection analysis mass spectrometry using positive APCI ionizationon a Finnigan LCQ using 70:30 methanol:10 mM NH₄OH(aq) at a flow rate of0.8 mL/minutes. Loop-injection mass spectra were acquired using aFinnigan LCQ running LCQ Navigator 1.2 software and a Gilson 215 liquidhandler for fraction injection controlled by an Abbott developed VisualBasic application to provide the title compound (97 mg, 0.193 mmol,46.7% yield)

Example 9bN-cyclopentyl-5-(2,4-difluorophenoxy)-2-[(ethylsulfonyl)amino]-4-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)benzamide

Using the procedure described for Example 1j and substituting Example 9afor Example 1i provided the title compound. ¹H NMR (300 MHz, DMSO-d₆) δ12.11 (s, 1H), 11.04 (s, 1H), 8.70 (d, J=7.1 Hz, 1H), 7.71 (s, 1H), 7.65(s, 1H), 7.41-7.24 (m, 3H), 6.94-6.80 (m, 2H), 6.32-6.19 (m, 1H), 4.21(dd, J=13.7, 7.0 Hz, 1H), 3.51 (s, 3H), 3.24 (q, J=7.1 Hz, 2H),1.98-1.80 (m, 2H), 1.67 (s, 2H), 1.54 (d, J=9.2 Hz, 4H), 1.20 (t, J=7.3Hz, 3H). MS (ESI+) m/z 571.2 (M+H)⁺.

Example 105-(2,4-difluorophenoxy)-2-[(ethylsulfonyl)amino]-N,N-dimethyl-4-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)benzamideExample 10a4-bromo-5-(2,4-difluorophenoxy)-2-(ethylsulfonamido)-N,N-dimethylbenzamide

Using the procedure described for Example 9a and substitutingdimethylamine for cyclopentanamine provided the title compound.

Example 10b5-(2,4-difluorophenoxy)-2-[(ethylsulfonyl)amino]-N,N-dimethyl-4-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)benzamide

Using the procedure described for Example 1j and substituting Example10a for Example 1i provided the title compound. ¹H NMR (400 MHz,DMSO-d₆) δ 12.07 (s, 1H), 9.19 (s, 1H), 7.53 (s, 1H), 7.45-7.35 (m, 2H),7.31 (t, J=2.8 Hz, 1H), 7.27-7.11 (m, 1H), 7.04 (ddd, J=9.3, 2.9, 1.5Hz, 1H), 6.75 (s, 1H), 6.37-6.31 (m, 1H), 3.55 (s, 3H), 3.12 (q, J=7.3Hz, 2H), 2.93 (s, 3H), 2.80 (d, J=9.8 Hz, 3H), 1.22 (t, J=7.3 Hz, 3H).MS (ESI+) m/z 531.1 (M+H)⁺.

Example 115-(2,4-difluorophenoxy)-2-[(ethylsulfonyl)amino]-4-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)benzoicacid

Using the procedure described for Example 1j and substituting Example 2dfor Example 1i provided the title compound. ¹H NMR (300 MHz, DMSO-d₆) δ12.16-12.07 (m, 1H), 10.71-10.52 (m, 1H), 7.76 (s, 1H), 7.49-7.38 (m,3H), 7.32 (t, J=2.8 Hz, 1H), 7.23 (td, J=9.2, 5.5 Hz, 1H), 7.11-7.00 (m,1H), 6.32 (t, J=2.3 Hz, 1H), 3.56 (s, 3H), 1.21 (t, J=7.3 Hz, 3H). MS(ESI+) m/z 504.1 (M+H)⁺.

Example 125-(2,4-difluorophenoxy)-2-[(ethylsulfonyl)amino]-4-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-N-(tetrahydro-2H-pyran-4-yl)benzamideExample 12a4-bromo-5-(2,4-difluorophenoxy)-2-(ethylsulfonamido)-N-(tetrahydro-2H-pyran-4-yl)benzamide

Using the procedure described for Example 9a and substitutingtetrahydro-2H-pyran-4-amine (CAS 38041-19-9) for cyclopentanamineprovided the title compound.

Example 12b5-(2,4-difluorophenoxy)-2-[(ethylsulfonyl)amino]-4-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-N-(tetrahydro-2H-pyran-4-yl)benzamide

Using the procedure described for Example 1j and substituting Example12a for Example 1i provided the title compound. ¹H NMR (300 MHz,DMSO-d₆) δ 12.08 (s, 1H), 10.93 (s, 1H), 8.68 (d, J=7.6 Hz, 1H), 7.71(d, J=6.5 Hz, 1H), 7.61 (d, J=14.0 Hz, 1H), 7.36 (s, 1H), 7.33-7.24 (m,2H), 6.94-6.81 (m, 2H), 6.26 (dt, J=20.8, 10.4 Hz, 1H), 4.03 (dt,J=11.4, 4.7 Hz, 1H), 3.87 (d, J=9.9 Hz, 2H), 3.49 (d, J=9.1 Hz, 3H),3.39 (dd, J=7.6, 5.6 Hz, 2H), 3.23 (dd, J=8.9, 5.7 Hz, 2H), 1.76 (d,J=12.4 Hz, 2H), 1.64-1.46 (m, 2H), 1.21 (t, J=7.3 Hz, 3H). MS (ESI+) m/z587.5 (M+H)⁺.

Example 13N-[4-(2,4-difluorophenoxy)-2-{[(2-hydroxyethyl)amino]methyl}-5-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)phenyl]ethanesulfonamide

Example 13 was prepared according to the procedure used for thepreparation of Example 2h, substituting 2-aminoethanol fordimethylamine. ¹H NMR (400 MHz, DMSO-d₆) δ 12.02 (s, 1H), 7.46 (s, 1H),7.36 (ddd, J=11.4, 8.9, 2.9 Hz, 1H), 7.28 (d, J=4.4 Hz, 2H), 7.10-6.94(m, 2H), 6.90 (s, 1H), 6.26 (s, 1H), 3.87 (s, 2H), 3.55-3.48 (m, 3H),3.49-3.43 (m, 4H), 3.15 (dd, J=14.6, 7.3 Hz, 2H), 2.59 (t, J=5.6 Hz,2H), 1.24 (t, J=7.3 Hz, 3H). MS (ESI+) m/z 532.9 (M+H)⁺.

Example 14N-{4-(2,4-difluorophenoxy)-5-(6-methyl-7-oxo-6,7-dihydro-H-pyrrolo[2,3-c]pyridin-4-yl)-2-[(2-phenylpyrrolidin-1-yl)methyl]phenyl}ethanesulfonamideExample 14aN-(5-bromo-4-(2,4-difluorophenoxy)-2-((2-phenylpyrrolidin-1-yl)methyl)phenyl)ethanesulfonamide

Example 14a was prepared according to the procedure used for thepreparation of Example 2h, substituting Example 2f for Example 2g andsubstituting 2-phenylpyrrolidine for dimethylamine.

Example 14bN-{4-(2,4-difluorophenoxy)-5-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-2-[(2-phenylpyrrolidin-1-yl)methyl]phenyl}ethanesulfonamide

Using the procedure described for Example 1j and substituting Example14a for Example 1i provided the title compound. ¹H NMR (400 MHz,DMSO-d₆) δ 12.03 (s, 1H), 7.58 (d, J=10.0 Hz, 1H), 7.48-7.38 (m, 2H),7.37-7.14 (m, 7H), 7.06 (dt, J=32.8, 15.9 Hz, 2H), 6.92 (s, 1H), 6.22(d, J=20.1 Hz, 1H), 3.66 (d, J=14.3 Hz, 1H), 3.52 (s, 4H), 2.92 (dtd,J=28.7, 14.3, 7.1 Hz, 3H), 2.34-2.08 (m, 2H), 1.77 (dd, J=28.3, 17.5 Hz,4H), 1.07 (t, J=7.2 Hz, 3H). MS (ESI+) m/z 617.2 (M+H)⁺.

Example 15N-[3-cyclopropyl-4-(2,4-difluorophenoxy)-5-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)phenyl]ethanesulfonamideExample 15a 1,3-dibromo-2-(2,4-difluorophenoxy)-5-nitrobenzene

A solution of 1,3-dibromo-2-fluoro-5-nitrobenzene (2.38 g, 7.80 mmol),2,4-difluorophenol (1.025 g, 7.80 mmol) and potassium carbonate (2.70 g,19.51 mmol) in dimethylformamide (20 mL) was stirred at 75° C. for 3hours. The reaction mixture was cooled to ambient temperature andpartitioned between ethyl acetate and dilute sodium chloride solution.The ethyl acetate layer was dried with anhydrous magnesium sulfate,filtered, and concentrated. The residue was recrystallized fromdiethylether and heptane, filtered, and dried in a vacuum oven at 50° C.to provide 3.02 g (95%) of the title compound.

Example 15b 1-bromo-3-cyclopropyl-2-(2,4-difluorophenoxy)-5-nitrobenzene

Example 15a (3.61 g, 8.83 mmol), cyclopropylboronic acid (0.76 g, 8.83mmol), and cesium carbonate (8.63 g, 26.5 mmol) were combined andsparged with argon for 10 minutes. Dioxane (50 mL) and water (10 mL)were added and argon was bubbled through the mixture for 15 minutes. Tothe resulting mixture was added bis(triphenylphosphine)palladium(II)chloride (0.434 g, 0.618 mmol), and the reaction mixture was stirredunder argon at 105° C. for 5 hours. To the cooled reaction mixture wasadded dilute ammonium chloride solution and the mixture was extractedtwice with ethyl acetate. The combined organic layers were dried withanhydrous magnesium sulfate, filtered, and concentrated. The residue waspurified twice by chromatography (silica gel, 4-6% dichloromethane inheptane) to afford 0.55 g (17%) of the title compound.

Example 15c 3-bromo-5-cyclopropyl-4-(2,4-difluorophenoxy)aniline

A solution of Example 15b (0.467 g, 1.262 mmol) and ammonium chloride(0.675 g, 12.6 mmol) in ethanol (25 mL), tetrahydrofuran (10 mL) andwater (5 mL) was stirred at 0° C. Powdered zinc (1.237 g, 18.92 mmol)was added and the mixture was stirred at 0° C. for 15 minutes and thenallowed to warm slowly to ambient temperature and stirred for 3 hours.The reaction mixture was filtered through Celite and rinsed with waterand dichloromethane. The organic phase was separated, dried withanhydrous magnesium sulfate, filtered, and concentrated to afford 0.40 g(93%) of the title compound.

Example 15dN-(3-bromo-5-cyclopropyl-4-(2,4-difluorophenoxy)phenyl)ethanesulfonamide

A solution of Example 15c (0.40 g, 1.18 mmol) and triethylamine (0.66mL, 4.70 mmol) in dichloromethane (140 mL) was stirred at 0° C. To thissolution was added ethanesulfonyl chloride (0.34 mL, 3.53 mmol). Thereaction mixture was allowed to warm to ambient temperature and stirredfor 3 hours. The reaction mixture was concentrated to provide a crudecrystalline solid. The resulting solid residue was dissolved in dioxane(16 mL) and stirred at ambient temperature. A 10% sodium hydroxidesolution (8.0 mL) was added and the mixture was stirred at 95° C. for 1hour. The reaction mixture was cooled to ambient temperature and diluteammonium chloride solution added until pH was about 7. The mixture wasextracted twice with ethyl acetate, dried with anhydrous magnesiumsulfate, filtered, and concentrated. The residue was purified bychromatography (silica gel, 20% heptane in dichloromethane) to provide0.48 g (94%) of the title compound.

Example 15eN-[3-cyclopropyl-4-(2,4-difluorophenoxy)-5-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)phenyl]ethanesulfonamide

Example 15d (0.438 g, 1.013 mmol), Example 1f (0.456 g, 1.064 mmol),tetrakis(triphenylphosphine)palladium (0) (0.117 g, 0.101 mmol), andcesium fluoride (0.462 g, 3.040 mmol) were combined and sparged withargon for 10 minutes. Dimethoxyethane (10 mL) and methanol (5 mL) wereadded and argon was bubbled through the mixture for 15 minutes. Thereaction mixture was stirred at 120° C. for 50 minutes. To the cooledreaction mixture was added 5N sodium hydroxide aqueous solution (4 mL)and the mixture was stirred for 2 hours at ambient temperature. To theresulting mixture was added dilute ammonium chloride solution andextracted twice with ethyl acetate. The combined organic layers weredried with anhydrous magnesium sulfate, filtered, and concentrated. Theresidue was purified by chromatography (silica gel, 33% heptane in ethylacetate) to provide 0.33 g (65%) of the title compound. ¹H NMR (400 MHz,DMSO-d₆) δ 11.99 (s, 1H), 9.79 (s, 1H), 7.29-7.22 (m, 3H), 7.21-7.13 (m,1H), 6.84 (d, J=2.6 Hz, 1H), 6.76-6.67 (m, 1H), 6.51-6.40 (m, 1H), 6.17(t, J=2.3 Hz, 1H), 3.46 (s, 3H), 3.13 (q, J=7.3 Hz, 2H), 1.99-1.88 (m,1H), 1.23 (t, J=7.3 Hz, 3H), 0.93-0.83 (m, 2H), 0.66-0.57 (m, 2H). MS(ESI+) m/z 500.1 (M+H)⁺.

Example 164-{2-[(2,2-difluorocyclopropyl)methoxy]-5-(ethylsulfonyl)phenyl}-6-methyl-2-{[4-(pyridin-4-yl)piperazin-1-yl]methyl}-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-oneExample 16a (Z)-ethyl3-(5-bromo-2-methoxy-3-nitropyridin-4-yl)-2-hydroxyacrylate

To a solution of ethanol (15 mL) and ether (150 mL) were added5-bromo-2-methoxy-4-methyl-3-nitropyridine (14.8 g, 60 mmol), diethyloxalate (13.2 g, 90 mmol), and potassium ethoxide (6.06 g, 72 mmol). Thereaction mixture was heated at 45° C. for 24 hours. During this period,the flask was shaken by hand several times. After cooling to ambienttemperature, the reaction mixture was partitioned between water andethyl acetate. The aqueous layer was extracted with additional ethylacetate three times. The combined organic layers were washed withsaturated aqueous sodium chloride, dried over anhydrous magnesiumsulfate, filtered, and concentrated. The residue was purified by flashchromatography (silica gel, 10-20% ethyl acetate in hexanes) to provide9.5 g of the title compound (yield 46%).

Example 16b ethyl4-bromo-7-methoxy-1H-pyrrolo[2,3-c]pyridine-2-carboxylate

A mixture Example 16a (9.5 g, 27.4 mmol) and iron powder (7.64 g, 137mmol) in ethanol (60 mL) and acetic acid (60 mL) was heated at 100° C.for 1 hour. The resulting solid was filtered off, and then washed withadditional ethyl acetate. The solvents were removed under reducedpressure to 20% of original volume, and the mixture was partitionedbetween water and ethyl acetate. The aqueous layer was extracted withadditional ethyl acetate several times. The combined organic layers werewashed with saturated aqueous sodium chloride, dried over anhydrousmagnesium sulfate, filtered, and concentrated. The residue was purifiedby flash chromatography (silica gel, 20-40% ethyl acetate in hexanes) toafford 6.05 g of the title compound.

Example 16c ethyl1-benzyl-4-bromo-7-methoxy-1H-pyrrolo[2,3-c]pyridine-2-carboxylate

Example 16b (0.88 g, 2.94 mmol) in dimethylformamide (15 mL) was treatedwith 60% sodium hydride (0.106 g, 4.41 mmol, 0.177 g of a 60% in oildispersion). The solution was stirred at ambient temperature for 10minutes. To this solution was added benzyl bromide (0.59 g, 3.45 mmol).The reaction mixture was stirred for another 2 hours and then waspartitioned between water and ethyl acetate. The aqueous layer wasextracted with additional ethyl acetate twice. The combined organiclayers were washed with saturated aqueous sodium chloride, dried overanhydrous magnesium sulfate, filtered, and concentrated. The residue waspurified by flash chromatography (silica gel, 20-40% ethyl acetate inhexanes) to afford 1.07 g of the title compound.

Example 16d ethyl1-benzyl-4-bromo-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-2-carboxylate

Example 16d was prepared according to the procedure used for thepreparation of Example 1d, substituting Example 16c for Example 1c.

Example 16e

Example 16e was prepared according to the procedure used for thepreparation of Example 1e, substituting Example 16d for Example 1d.

Example 16f ethyl1-benzyl-6-methyl-7-oxo-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-2-carboxylate

A mixture of Example 16e (2 g, 5.14 mmol), bis(pinacolato)diboron (2.61g, 10.3 mmol), potassium acetate (1.11 g, 11.3 mmol),tris(dibenzylideneacetone)dipalladium(0) (0.235 g, 0.257 mmol), and2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl (0.245 g, 0.514mmol) in dioxane (50 mL) was stirred at 90° C. for 16 hour under anargon atmosphere. The mixture was filtered through Celite, washed withethyl acetate several times and concentrated. The residue was purifiedby flash chromatography (silica gel, 50-75% ethyl acetate/petroleumether gradient) to afford the title compound (1.15 g, 40% yield).

Example 16g ethyl(4-fluorophenyl)sulfane

Triethylamine (5.44 mL, 39 mmol) was added to a solution of4-fluorobenzenethiol (5 g, 39 mmol) and iodoethane (3.78 mL, 46.8 mmol)in tetrahydrofuran (50 mL). The resulting mixture was stirred at ambienttemperature for 2 hours and then filtered. The filtrate was concentratedand then triturated with hexane, and the resulting solid was dried undervacuum to afford the title compound (4.8 g, 76%).

Example 16h 1-(ethylsulfonyl)-4-fluorobenzene

Example 16g (5 g, 32 mmol) in dichloromethane (200 mL) was treated with3-chloroperoxybenzoic acid (14.3 g, 70.4 mmol) and stirred at ambienttemperature for 6 hours.

The solid formed during the reaction mixture was removed by filtrationand washed with additional dichloromethane. The combined filtrate waswashed with 10% aqueous sodium hydroxide solution (50 mL, twice) andsaturated aqueous sodium bicarbonate solution, dried over anhydroussodium sulfate, filtered, and concentrated. The residue was purified byflash chromatography (silica gel, 15% ethyl acetate in petroleum ether)to afford the title compound (4.6 g, 76%).

Example 16i 2-bromo-4-(ethylsulfonyl)-1-fluorobenzene

Example 16h (1 g, 5.31 mmol) in concentrated H₂SO₄ (6 mL) was treatedwith N-bromosuccinimide (1.040 g, 5.84 mmol). The reaction mixture wasstirred at ambient temperature for 6 hours, and then was stirred at 50°C. for 12 hours. The reaction mixture was poured into ice-water. Theresulting solid was collected by filtration. The solid was washed withcold water three times, and dried in a vacuum oven overnight. It wasthen purified by flash chromatography (silica gel, 10:1 to 4:1 petroleumether/ethyl acetate gradient) to afford the title compound (1.1 g, 4.12mmol, 78% yield).

Example 16j ethyl1-benzyl-4-(5-(ethylsulfonyl)-2-fluorophenyl)-6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-2-carboxylate

A mixture of Example 16f (1.53 g, 3.51 mmol), Example 16i (1.030 g, 3.86mmol), 1,3,5,7-tetramethyl-6-phenyl-2,4,8-trioxa-6-phosphaadamantane(0.103 g, 0.351 mmol), Pd₂(dba)₃ (0.080 g, 0.088 mmol) and K₃PO₄ (1.861g, 8.77 mmol) was sparged with argon for 30 minutes. A mixture ofdioxane (20 mL) and water (5 mL) was also sparged with nitrogen for 30minutes and transferred by syringe into the reaction vessel under argon.The reaction mixture was stirred at 60° C. for 16 hours, cooled toambient temperature, and partitioned between ethyl acetate and water.The organic layer was extracted with additional ethyl acetate twice. Thecombined organic layers were washed with saturated aqueous sodiumchloride, dried over anhydrous sodium sulfate, filtered, andconcentrated. Purification by flash chromatography (silica gel,petroleum ether/ethyl acetate gradient, 5/1 to 2/1) afforded the titlecompound (1.92 g, 2.46 mmol, 70% yield).

Example 16k ethyl4-(5-(ethylsulfonyl)-2-fluorophenyl)-6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-2-carboxylate

A mixture of Example 16j (3.56 g, 7.17 mmol), anisole (1.566 mL, 14.34mmol) and H₂SO₄ (3.5 mL, 65.7 mmol) in trifluoroacetic acid (70 mL, 909mmol) was heated at 90° C. for 4 hours. Excess trifluoroacetic acid wasremoved under reduced pressure, and the residue was partitioned betweenwater (10 mL) and ethyl acetate (40 mL). The organic layer wasseparated, and the aqueous layer was extracted with additional ethylacetate twice (80 mL). The combined organic layers were washed withsaturated aqueous sodium bicarbonate (20 mL), followed by saturatedaqueous sodium chloride (20 mL), dried over anhydrous magnesium sulfate,filtered, and concentrated. The crude residue was treated with methanol(10 mL) and the solid was filtered and dried under vacuum to give thetitle compound (3.1 g, 6.25 mmol, 87% yield).

Example 161 ethyl4-(2-((2,2-difluorocyclopropyl)methoxy)-5-(ethylsulfonyl)phenyl)-6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-2-carboxylate

A solution of Example 16k (0.8 g, 1.968 mmol) and(2,2-difluorocyclopropyl)methanol (0.426 g, 3.94 mmol) indimethylsulfoxide (10 mL) was treated with Cs₂CO₃ (0.962 g, 2.95 mmol).The reaction mixture was heated at 110° C. for 5 days. During the 5days, three additional batches of (2,2-difluorocyclopropyl)methanol(0.426 g, 3.94 mmol) were added into the reaction mixture. The reactionmixture was cooled to ambient temperature and poured into ethyl acetate(100 mL) and water (100 mL). The aqueous layer was extracted with ethylacetate (100 mL, twice). The combined organic layers were dried overanhydrous sodium sulfate, filtered, and concentrated to give the titlecompound (0.9 g, 1.820 mmol, 92% yield) which was used in the next stepwithout additional purification.

Example 16m4-(2-((2,2-difluorocyclopropyl)methoxy)-5-(ethylsulfonyl)phenyl)-2-(hydroxymethyl)-6-methyl-1H-pyrrolo[2,3-c]pyridin-7(6H)-one

Example 161 (1.8 g, 3.64 mmol) in tetrahydrofuran (20 mL) at 0° C. wastreated with LiAlH₄ (1 M in tetrahydrofuran) (3.64 mL, 3.64 mmol)dropwise. The reaction mixture was stirred at 0° C. for 2 hours. Thereaction mixture was poured into ethyl acetate (100 mL) and water (80mL) and the mixture was filtered through Celite. The organic layer wasseparated and the aqueous layer was extracted with ethyl acetate (50 mL,twice). The combined organic layers were dried over anhydrous sodiumsulfate, filtered, and concentrated. The crude was purified by flashchromatography (silica gel, ethyl acetate to 30/1dichlormethane/methanol gradient) to provide the title compound (0.6 g,1.074 mmol, 29.5% yield).

Example 16n4-(2-((2,2-difluorocyclopropyl)methoxy)-5-(ethylsulfonyl)phenyl)-6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-2-carbaldehyde

To the solution of Example 16m (0.5 g, 1.105 mmol) in dichloromethane(20 mL) at 0° C. was added Dess-Martin Periodinane (0.937 g, 2.210 mmol)and the mixture was stirred at 0° C. for 30 minutes. Then the reactiontemperature was allowed to warm to ambient temperature. After 3 hours asolution of Na₂S₂O₃ in saturated aqueous NaHCO₃ (5 mL) was added to thereaction mixture. The mixture was stirred for 15 minutes and extractedwith ethyl acetate. The organic layer was dried over anhydrous magnesiumsulfate, filtered, and concentrated to give the title compound (0.6 g,0.759 mmol, 68.7% yield).

Example 16o4-{2-[(2,2-difluorocyclopropyl)methoxy]-5-(ethylsulfonyl)phenyl}-6-methyl-2-{[4-(pyridin-4-yl)piperazin-1-yl]methyl}-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one

To a solution of Example 16n (0.10 g, 0.22 mmol) and1-(pyridin-4-yl)piperazine (0.072 g, 0.44 mmol) in methanol (6 mL) wasadded zinc chloride (0.030 g, 0.22 mmol) at ambient temperature. Thereaction mixture was stirred for 1 hour, followed by the addition ofNaCNBH₄ (0.028 g, 0.444 mmol), and the reaction mixture was stirred at25° C. overnight. The reaction mixture was concentrated and the crudematerial was purified by reverse phase Prep HPLC (C18, 20-50%acetonitrile in 0.01 N NH₄CO₃/water) to give the title compound (31 mg,0.050 mmol, 22.34% yield). ¹H NMR (400 MHz, DMSO-d₆) δ 11.99 (s, 1H),8.13 (s, 2H), 7.98-7.71 (m, 2H), 7.46-7.30 (m, 2H), 6.76 (d, J=5.6 Hz,2H), 6.05 (d, J=1.6 Hz, 1H), 4.30-4.16 (m, 2H), 3.64 (s, 2H), 3.57 (s,3H), 3.33-3.20 (m, 6H), 2.51-2.48 (m, 4H), 2.19-2.04 (m, 1H), 1.68-1.63(m, 1H), 1.55-1.38 (m, 1H), 1.13 (t, J=7.3 Hz, 3H). MS (ESI+) m/z 598.2(M+H)⁺.

Example 174-{2-[(2,2-difluorocyclopropyl)methoxy]-5-(ethylsulfonyl)phenyl}-6-methyl-2-{[4-(1,3-thiazol-2-yl)piperazin-1-yl]methyl}-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one

Example 17 was prepared according to the procedure used for thepreparation of Example 16o, substituting 2-(piperazin-1-yl)thiazole for1-(pyridin-4-yl)piperazine. ¹H NMR (400 MHz, DMSO-d₆) δ 11.98 (s, 1H),7.88-7.77 (m, 2H), 7.41-7.33 (m, 2H), 7.13 (d, J=3.6 Hz, 1H), 6.82 (d,J=3.6 Hz, 1H), 6.05 (s, 1H), 4.30-4.14 (m, 2H), 3.64 (s, 2H), 3.56 (s,3H), 3.35 (s, 4H), 3.28 (q, J=7.3 Hz, 2H), 2.46 (s, 4H), 2.18-2.08 (m,1H), 1.71-1.59 (m, 1H), 1.53-1.41 (m, 1H), 1.12 (t, J=7.3 Hz, 3H). MS(ESI+) m/z 604.3 (M+H)⁺.

Example 184-{2-[(2,2-difluorocyclopropyl)methoxy]-5-(ethylsulfonyl)phenyl}-6-methyl-2-{[4-(pyrazin-2-yl)piperazin-1-yl]methyl}-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one

Example 18 was prepared according to the procedure used for thepreparation of Example 16o, substituting 2-(piperazin-1-yl)pyrazine for1-(pyridin-4-yl)piperazine. ¹H NMR (400 MHz, DMSO-d₆) δ 11.98 (s, 1H),8.27 (s, 1H), 8.05 (s, 1H), 7.88-7.77 (m, 3H), 7.42-7.32 (m, 2H), 6.05(s, 1H), 4.31-4.14 (m, 2H), 3.64 (s, 2H), 3.56 (s, 3H), 3.54-3.44 (m,4H), 3.29 (q, J=7.4 Hz, 2H), 2.48-2.44 (m, 4H), 2.20-2.05 (m, 1H),1.71-1.57 (m, 1H), 1.51-1.39 (m, 1H), 1.12 (t, J=7.3 Hz, 3H). MS (ESI+)m/z 599.3 (M+H)⁺.

Example 194-{2-[(2,2-difluorocyclopropyl)methoxy]-5-(ethylsulfonyl)phenyl}-6-methyl-2-{[4-(pyrimidin-2-yl)piperazin-1-yl]methyl}-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one

Example 19 was prepared according to the procedure used for thepreparation of Example 16o, substituting 2-(piperazin-1-yl)pyrimidinefor 1-(pyridin-4-yl)piperazine. ¹H NMR (400 MHz, DMSO-d₆) δ 11.98 (s,1H), 8.32 (d, J=4.7 Hz, 2H), 7.87-7.78 (m, 2H), 7.41-7.32 (m, 2H), 6.59(t, J=4.7 Hz, 1H), 6.04 (s, 1H), 4.30-4.15 (m, 2H), 3.73-3.64 (m, 4H),3.62 (s, 2H), 3.56 (s, 3H), 3.28 (q, J=7.3 Hz, 2H), 2.45-2.37 (m, 4H),2.20-2.05 (m, 1H), 1.73-1.56 (m, 1H), 1.53-1.40 (m, 1H), 1.13 (t, J=7.3Hz, 3H). MS (ESI+) m/z 599.3 (M+H)⁺.

Example 204-{2-[(2,2-difluorocyclopropyl)methoxy]-5-(ethylsulfonyl)phenyl}-6-methyl-2-{[4-(pyridin-3-yl)piperazin-1-yl]methyl}-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one

Example 20 was prepared according to the procedure used for thepreparation of Example 16o, substituting 1-(pyridin-3-yl)piperazine for1-(pyridin-4-yl)piperazine. ¹H NMR (400 MHz, CD3OD) δ 8.19 (d, J=2.8 Hz,1H), 7.94 (d, J=3.5 Hz, 1H), 7.91-7.89 (m, 2H), 7.39-7.36 (m, 1H),7.34-7.31 (m, 2H), 7.27-7.23 (m, 1H), 6.18 (s, 1H), 4.31-4.29 (m, 1H),4.15-4.10 (m, 1H), 3.74 (s, 2H), 3.68 (s, 3H), 3.28-3.19 (m, 6H),2.67-2.64 (m, 4H), 2.03-2.01 (m, 1H), 1.60-1.46 (m, 1H), 1.28-1.26 (m,1H), 1.24 (t, J=7.4 Hz, 3H). MS (ESI+) m/z 598.3 (M+H)⁺.

Example 21N-cyclopropyl-3-[2-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-4-(methylsulfonyl)phenoxy]benzamideExample 21a (3-bromo-4-fluorophenyl)(methyl)sulfane

A solution of 3-bromo-4-fluorobenzenethiol (CAS 942473-85-0) (10 g, 48.3mmol) in methanol (105 mL) was stirred at 0° C. as 5M sodium hydroxidesolution (10 mL, 50.0 mmol) was added. After 10 min at 0° C.,iodomethane (3.6 mL, 57.6 mmol) was added and the reaction mixture wasstirred at ambient temperature overnight. The reaction mixture wasconcentrated under reduced pressure and 500 mL ethyl acetate was addedto the residue. The solution was washed with water, saturated aqueoussodium chloride, dried (anhydrous sodium sulfate), filtered, andconcentrated to provide the title compound (10.75 g, 48.6 mmol, 100%yield).

Example 21b 2-bromo-1-fluoro-4-(methylsulfonyl)benzene

3-Chlorobenzoperoxoic acid (26.3 g, 152 mmol) was added portionwise to asolution of Example 21a (10.75 g, 48.6 mmol) in dichloromethane (500mL). The reaction mixture was stirred at ambient temperature for 6hours. The solid was filtered and was rinsed with dichloromethane. Thecombined filtrate was washed with 10% aqueous NaOH, saturated sodiumbicarbonate solution, and saturated aqueous sodium chloridesequentially, dried (anhydrous sodium sulfate), filtered, andconcentrated to afford 11.6 g white solid. The crude product waspurified by flash chromatography (silica gel, eluting with heptanescontaining a gradient of ethyl acetate, 5-45%) to provide the titlecompound (11.09 g, 43.8 mmol, 90% yield).

Example 21c methyl 3-(2-bromo-4-(methylsulfonyl)phenoxy)benzoate

A mixture of Example 21b (50 mg, 0.198 mmol), methyl 3-hydroxybenzoate(CAS 19438-10-9, 36 mg, 0.237 mmol), cesium carbonate (92 mg, 0.282mmol) and dimethylsulfoxide (0.8 mL) was heated in a sealed tube at 120°C. for 45 minutes. The reaction mixture was cooled to ambienttemperature and water (50 mL) was added with rapid stirring to obtain afinely dispersed white solid. The mixture was extracted with ethylacetate. The organic layer was washed with water, saturated aqueoussodium chloride, dried (anhydrous magnesium sulfate), filtered, andconcentrated to provide the title compound (40 mg, 0.104 mmol, 53%yield)

Example 21d3-[2-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-4-(methylsulfonyl)phenoxy]benzoicacid

A nitrogen degassed solution of Example 21c (690 mg, 1.791 mmol),Example 1f (767 mg, 1.791 mmol), cesium fluoride (812 mg, 5.35 mmol),(tetrakistriphenylphosphine)palladium(0) (106 mg, 0.092 mmol),dimethoxyethane (8.5 mL) and methanol (4.1 mL) was heated in themicrowave at 120° C. for 40 minutes. Water (50 mL) was added and themixture was extracted with ethyl acetate. The organic layer was washedwith saturated aqueous sodium chloride, dried (anhydrous magnesiumsulfate), filtered, and concentrated to afford 1.1 g of yellow foam. Thecrude product was absorbed onto silica gel and purified by flashchromatography (silica gel, eluting with dichloromethane containing agradient with methanol, 1% to 8%) to provide a 1:1 mixture of tosylatedand non-tosylated products. The mixture of products was stirred atreflux for 6 hours with sodium hydroxide (80 mg, 2.000 mmol), ethanol(8.0 mL) and water (0.3 mL). The reaction mixture was cooled to 0° andwater (20 mL) was added slowly with stirring, followed by the additionof 5% aqueous citric acid to about pH5. After stirring at 0° for 30minutes the aqueous slurry was filtered, rinsed with water, and dried(in-vacuo) to provide the title compound.

Example 21eN-cyclopropyl-3-[2-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-4-(methylsulfonyl)phenoxy]benzamide

A solution of Example 21d (88 mg, 0.201 mmol), cyclopropanamine (0.014mL, 0.201 mmol), 1H-benzo[d][1,2,3]triazol-1-ol hydrate (36 mg, 0.235mmol) and dimethylformamide (1.9 mL) was stirred at ambient temperature.After addingN1-((ethylimino)methylene)-N3,N3-dimethylpropane-1,3-diaminehydrochloride (46 mg, 0.240 mmol) and N-ethyl-N-isopropylpropan-2-amine(0.087 mL, 0.498 mmol) the reaction mixture was stirred at ambienttemperature overnight. The reaction mixture was cooled to 0° C. and icewater (20 mL) was added slowly with rapid stirring. The resulting solidwas filtered, rinsed with water and was dried (in vacuo) to provide thetitle compound (70 mg, 0.147 mmol, 73% yield). ¹H NMR (300 MHz, DMSO-d₆)δ 12.24-11.86 (m, 1H), 8.52-8.35 (m, 1H), 8.05-7.96 (m, 1H), 7.94-7.80(m, 1H), 7.74-7.59 (m, 1H), 7.55-7.51 (m, 1H), 7.51-7.44 (m, 1H),7.44-7.40 (m, 1H), 7.29 (t, J=2.8 Hz, 1H), 7.28-7.23 (m, 1H), 7.12-6.91(m, 1H), 6.35-5.80 (m, 1H), 3.62-3.50 (m, 3H), 3.25 (d, J=7.9 Hz, 3H),2.87-2.76 (m, 1H), 0.72-0.61 (m, 2H), 0.59-0.45 (m, 2H). MS (ESI+) m/z478.1 (M+H)⁺.

Example 226-methyl-4-[2-{3-[(4-methylpiperazin-1-yl)carbonyl]phenoxy}-5-(methylsulfonyl)phenyl]-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one

A stock solution of Example 21d and DIPEA (0.19 M and 0.54 M in DMA,respectively, 181 μL, 0.034 mmol Example 21d (1.0 equivalent) and 0.102mmol DIPEA (3.0 equivalents)), HATU (0.28 M in DMA, 181 μL, 0.051 mmol,1.5 equivalents), and 1-methylpiperazine (0.40 M in DMA, 103 μL, 0.041mmol, 1.2 equivalents) were aspirated from their respective sourcevials, mixed through a perfluoroalkoxy mixing tube (0.2 mm innerdiameter), and loaded into an injection loop. The reaction segment wasinjected into the flow reactor (Hastelloy coil, 0.75 mm inner diameter,1.8 mL internal volume) set at 100° C., and passed through the reactorat 180 μL min⁻¹ (10 minute residence time). Upon exiting the reactor,the reaction mixture was loaded directly into an injection loop and waspurified by preparative HPLC on a Phenomenex Luna C8(2) 5 μm 100 Å AXIAcolumn (50 mm×21.2 mm). A gradient of acetonitrile (A) and 0.1%trifluoroacetic acid in water (B) was used, at a flow rate of 30mL/minutes (0-0.5 minutes 5% A, 0.5-6.5 minutes linear gradient 5-100%A, 6.5-8.5 minutes 100% A, 8.5-9.0 minutes linear gradient 100-5% A,9.0-10 minutes 5% A). A sample volume of 1.0 mL was injected directlyfrom the flow reactor stream to the HPLC system. A custom purificationsystem was used, consisting of the following modules: Gilson 305 and 306pumps; Gilson 806 Manometric module; Gilson UV/Vis 155 detector; Gilson506C interface box; Gilson FC204 fraction collector; Agilent G1968DActive Splitter; Thermo MSQ Plus mass spectrometer. The system wascontrolled through a combination of Thermo Xcalibur 2.0.7 software and acustom application written in-house using Microsoft Visual Basic 6.0. toprovide the TFA salt of the title compound (14.71 mg, 68% yield). ¹H NMR(400 MHz, DMSO-d₆/D₂O) δ 8.01 (d, J=2.4 Hz, 1H), 7.93 (dd, J=8.6, 2.4Hz, 1H), 7.43 (t, J=7.9 Hz, 1H), 7.30 (d, J=1.6 Hz, 2H), 7.24 (d, J=8.6Hz, 1H), 7.18 (d, J=7.7 Hz, 1H), 7.09 (dd, J=8.2, 2.5 Hz, 1H), 7.01 (d,J=1.5 Hz, 1H), 6.25 (d, J=2.9 Hz, 1H), 3.65 (s, 2H), 3.53 (d, J=12.5 Hz,3H), 3.25-3.16 (m, 7H), 2.84 (s, 3H). MS (APCI+) m/z 621.2 (M+H)⁺.

Example 234-{2-[3-({4-[2-(1H-imidazol-1-yl)ethyl]piperazin-1-yl}carbonyl)phenoxy]-5-(methylsulfonyl)phenyl}-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one

The TFA salt of the title compound was prepared using the proceduredescribed for Example 22, substituting1-(2-(1H-imidazol-1-yl)ethyl)piperazine for 1-methylpiperazine andpurified by preparative HPLC on a Phenomenex Luna C8(2) 5 μm 100 Å AXIAcolumn (50 mm×21.2 mm) as described. A gradient of acetonitrile (A) and0.1% trifluoroacetic acid in water (B) was used, at a flow rate of 30mL/minutes (0-0.5 minutes 5% A, 0.5-6.5 minutes linear gradient 5-60% A,6.5-7.0 minutes linear gradient 60-100% A, 7.0-8.9 minutes 100% A,8.9-9.0 minutes linear gradient 100-5% A, 9.0-10 minutes 5% A). A samplevolume of 1.0 mL was injected directly from the flow reactor stream tothe HPLC system. A custom purification system was used, consisting ofthe following modules: Gilson 305 and 306 pumps; Gilson 806 Manometricmodule; Gilson UV/Vis 155 detector; Gilson 506C interface box; GilsonFC204 fraction collector; Agilent G1968D Active Splitter; Thermo MSQPlus mass spectrometer. The system was controlled through a combinationof Thermo Xcalibur 2.0.7 software and a custom application writtenin-house using Microsoft Visual Basic 6.0. ¹H NMR (400 MHz, DMSO-d₆/D₂O)δ 8.95 (s, 1H), 8.01 (d, J=2.4 Hz, 1H), 7.93 (dd, J=8.6, 2.4 Hz, 1H),7.68 (s, 1H), 7.57 (s, 1H), 7.40 (t, J=7.9 Hz, 1H), 7.29 (d, J=2.8 Hz,2H), 7.24 (d, J=8.6 Hz, 1H), 7.10 (d, J=7.6 Hz, 1H), 7.04 (dd, J=8.3,2.4 Hz, 1H), 6.90 (s, 1H), 6.24 (d, J=2.8 Hz, 1H), 4.38 (t, J=6.1 Hz,2H), 3.54 (s, 3H), 3.42 (s, 4H), 3.22 (s, 3H), 2.97 (t, J=6.2 Hz, 2H),2.62 (s, 4H). MS (APCI+) m/z 602.1 (M+H)⁺.

Example 246-methyl-4-[5-(methylsulfonyl)-2-(3-{[4-(pyrrolidin-1-yl)piperidin-1-yl]carbonyl}phenoxy)phenyl]-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one

The TFA salt of the title compound was prepared using the proceduredescribed for Example 22, substituting 4-(pyrrolidin-1-yl)piperidine for1-methylpiperazine and purified using method described in Example 23. ¹HNMR (400 MHz, DMSO-d₆/D₂O) δ 8.01 (d, J=2.4 Hz, 1H), 7.93 (dd, J=8.6,2.4 Hz, 1H), 7.41 (t, J=7.9 Hz, 1H), 7.30 (d, J=2.7 Hz, 2H), 7.24 (t,J=9.5 Hz, 1H), 7.11 (d, J=7.6 Hz, 1H), 7.05 (dd, J=8.2, 2.5 Hz, 1H),6.92 (d, J=1.5 Hz, 1H), 6.24 (d, J=2.8 Hz, 1H), 4.02 (d, J=38.8 Hz, 2H),3.54 (s, 4H), 3.50 (s, 1H), 3.39 (t, J=11.4 Hz, 1H), 3.23 (s, 3H), 3.15(s, 1H), 2.91 (t, J=12.5 Hz, 2H), 2.07 (d, J=12.3 Hz, 3H), 1.96 (s, 4H),1.51 (dt, J=11.9, 7.7 Hz, 2H). MS (APCI⁺) m/z 575.2 (M+H)⁺.

Example 25N-cyclohexyl-3-[2-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-4-(methylsulfonyl)phenoxy]benzamide

The TFA salt of the title compound was prepared using the proceduredescribed for Example 22, substituting cyclohexanamine for1-methylpiperazine, and purified by the method described in Example 23.¹H NMR (400 MHz, DMSO-d₆/D₂O) δ 8.00 (d, J=2.4 Hz, 1H), 7.90 (dd, J=8.6,2.4 Hz, 1H), 7.60 (d, J=7.7 Hz, 1H), 7.42 (dd, J=10.4, 5.4 Hz, 2H),7.36-7.27 (m, 2H), 7.14 (dd, J=8.3, 3.8 Hz, 2H), 6.26 (d, J=2.8 Hz, 1H),3.73 (s, 1H), 3.58-3.48 (m, 3H), 3.22 (d, J=4.3 Hz, 3H), 1.80 (s, 2H),1.73 (s, 2H), 1.59 (d, J=11.6 Hz, 1H), 1.40-1.23 (m, 4H), 1.15 (d, J=8.0Hz, 1H). MS (APCI+) m/z 519.8 (M+H)⁺.

Example 264-[2-(3-{[4-(2-hydroxyethyl)piperazin-1-yl]carbonyl}phenoxy)-5-(methylsulfonyl)phenyl]-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one

The TFA salt of the title compound was prepared using the proceduredescribed for Example 22, substituting 2-(piperazin-1-yl)ethanol for1-methylpiperazine, and purified by the method described in Example 23.¹H NMR (400 MHz, DMSO-d₆/D₂O) δ 8.01 (d, J=2.4 Hz, 1H), 7.93 (dd, J=8.6,2.4 Hz, 1H), 7.43 (t, J=7.9 Hz, 1H), 7.30 (d, J=2.7 Hz, 2H), 7.24 (d,J=8.6 Hz, 1H), 7.18 (d, J=7.6 Hz, 1H), 7.09 (dd, J=8.2, 2.5 Hz, 1H),7.02 (d, J=1.5 Hz, 1H), 6.25 (d, J=2.9 Hz, 1H), 3.81-3.76 (m, 2H), 3.69(s, 4H), 3.55 (s, 3H), 3.23 (d, J=8.4 Hz, 6H). MS (APCI+) m/z 551.1(M+H)⁺.

Example 273-[2-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-4-(methylsulfonyl)phenoxy]-N-[3-(2-oxopyrrolidin-1-yl)propyl]benzamide

The TFA salt of the title compound was prepared using the proceduredescribed for Example 22, substituting 1-(3-aminopropyl)pyrrolidin-2-onefor 1-methylpiperazine, and purified by the method described in Example23. ¹H NMR (400 MHz, DMSO-d₆/D₂O) δ 8.00 (d, J=2.4 Hz, 1H), 7.91 (dt,J=8.7, 4.5 Hz, 1H), 7.58 (t, J=12.6 Hz, 1H), 7.43 (t, J=7.9 Hz, 2H),7.33-7.27 (m, 2H), 7.15 (dd, J=12.9, 5.6 Hz, 2H), 6.26 (dd, J=6.2, 2.8Hz, 1H), 3.54 (d, J=5.2 Hz, 3H), 3.39-3.31 (m, 2H), 3.25-3.18 (m, 7H),2.22 (t, J=8.1 Hz, 2H), 1.99-1.85 (m, 2H), 1.72 (p, J=7.0 Hz, 2H). MS(APCI+) m/z 563.2 (M+H)⁺.

Example 284-[2-{3-[(4-cyclopentylpiperazin-1-yl)carbonyl]phenoxy}-5-(methylsulfonyl)phenyl]-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one

The TFA salt of the title compound was prepared using the proceduredescribed for Example 22, substituting 1-cyclopentylpiperazine for1-methylpiperazine, and purified by the method described in Example 23.¹H NMR (400 MHz, DMSO-d₆/D₂O) δ 8.01 (d, J=2.4 Hz, 1H), 7.93 (dd, J=8.6,2.4 Hz, 1H), 7.43 (t, J=7.9 Hz, 1H), 7.30 (d, J=2.9 Hz, 2H), 7.24 (d,J=8.6 Hz, 1H), 7.19 (d, J=7.6 Hz, 1H), 7.09 (dd, J=8.2, 2.4 Hz, 1H),7.03 (d, J=1.5 Hz, 1H), 6.25 (d, J=2.8 Hz, 1H), 3.59 (d, J=6.4 Hz, 4H),3.59-3.52 (m, 5H), 3.25-3.13 (m, 5H), 2.05 (d, J=8.0 Hz, 2H), 1.65 (dd,J=45.4, 8.2 Hz, 7H). MS (APCI+) m/z 575.2 (M+H)⁺.

Example 294-{2-[3-({4-[2-(dimethylamino)ethyl]piperazin-1-yl}carbonyl)phenoxy]-5-(methylsulfonyl)phenyl}-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one

The TFA salt of the title compound was prepared using the proceduredescribed for Example 22, substitutingN,N-dimethyl-2-(piperazin-1-yl)ethanamine for 1-methylpiperazine, andpurified by the method described in Example 23. ¹H NMR (400 MHz,DMSO-d₆/D₂O) δ 8.01 (d, J=2.4 Hz, 1H), 7.93 (dd, J=8.6, 2.4 Hz, 1H),7.41 (t, J=7.9 Hz, 1H), 7.30 (d, J=2.6 Hz, 2H), 7.24 (d, J=8.6 Hz, 1H),7.11 (d, J=7.7 Hz, 1H), 7.05 (dd, J=8.3, 2.4 Hz, 1H), 6.91 (d, J=1.5 Hz,1H), 6.25 (d, J=2.9 Hz, 1H), 3.54 (s, 3H), 3.44 (s, 4H), 3.26-3.20 (m,5H), 2.83 (s, 6H), 2.77 (t, J=6.2 Hz, 2H), 2.54 (dd, J=9.6, 3.7 Hz, 4H).MS (APCI+) m/z 578.2 (M+H)⁺.

Example 304-[2-{3-[(4-acetylpiperazin-1-yl)carbonyl]phenoxy}-5-(methylsulfonyl)phenyl]-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one

The TFA salt of the title compound was prepared using the proceduredescribed for Example 22, substituting 1-(piperazin-1-yl)ethanone for1-methylpiperazine, and purified by the method described in Example 23.¹H NMR (400 MHz, DMSO-d₆/D₂O) δ 8.00 (d, J=2.4 Hz, 1H), 7.93 (dd, J=8.6,2.4 Hz, 1H), 7.40 (t, J=7.9 Hz, 1H), 7.30 (d, J=4.0 Hz, 2H), 7.23 (t,J=10.1 Hz, 1H), 7.13 (d, J=7.6 Hz, 1H), 7.04 (dd, J=8.2, 2.5 Hz, 1H),6.94 (d, J=1.5 Hz, 1H), 6.25 (d, J=2.8 Hz, 1H), 3.54 (s, 3H), 3.46 (dd,J=11.7, 8.4 Hz, 4H), 3.41 (s, 4H), 3.22 (s, 3H), 2.02 (s, 3H). MS(APCI+) m/z 549.2 (M+H)⁺.

Example 316-methyl-4-[5-(methylsulfonyl)-2-(3-{[4-(trifluoromethyl)piperidin-1-yl]carbonyl}phenoxy)phenyl]-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one

The TFA salt of the title compound was prepared using the proceduredescribed for Example 22, substituting 4-(trifluoromethyl)piperidine for1-methylpiperazine, and purified by the method described in Example 23.¹H NMR (400 MHz, DMSO-d₆/D₂O) δ 8.00 (d, J=2.4 Hz, 1H), 7.92 (dd, J=8.6,2.4 Hz, 1H), 7.40 (t, J=7.9 Hz, 1H), 7.34-7.26 (m, 2H), 7.24 (d, J=8.6Hz, 1H), 7.11 (d, J=7.6 Hz, 1H), 7.04 (dd, J=8.2, 2.4 Hz, 1H), 6.92 (d,J=1.5 Hz, 1H), 6.25 (d, J=2.8 Hz, 1H), 4.02 (d, J=36.4 Hz, 2H), 3.54 (s,3H), 3.21 (d, J=7.5 Hz, 3H), 2.92 (t, J=12.1 Hz, 2H), 2.55 (d, J=5.7 Hz,1H), 1.83 (d, J=11.8 Hz, 2H), 1.38 (qd, J=12.4, 4.4 Hz, 2H). MS (APCI+)m/z 574.1 (M+H)⁺.

Example 32N-(cyanomethyl)-N-methyl-3-[2-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-4-(methylsulfonyl)phenoxy]benzamide

The TFA salt of the title compound was prepared using the proceduredescribed for Example 22, substituting 2-(methylamino)acetonitrile for1-methylpiperazine, and purified by the method described in Example 23.¹H NMR (400 MHz, DMSO-d₆/D₂O) δ 8.00 (d, J=2.4 Hz, 1H), 7.92 (dd, J=8.6,2.4 Hz, 1H), 7.43 (t, J=7.9 Hz, 1H), 7.34-7.28 (m, 2H), 7.25 (d, J=8.6Hz, 1H), 7.17 (d, J=7.7 Hz, 1H), 7.09 (dd, J=8.2, 2.5 Hz, 1H), 6.99 (d,J=1.6 Hz, 1H), 6.25 (d, J=2.8 Hz, 1H), 4.40 (s, 2H), 3.54 (s, 3H), 3.22(s, 3H), 2.93 (s, 3H). MS (APCI+) m/z 491.2 (M+H)⁺.

Example 33N-[2-(dimethylamino)ethyl]-3-[2-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-4-(methylsulfonyl)phenoxy]benzamide

The TFA salt of the title compound was prepared using the proceduredescribed for Example 22, substituting N1,N1-dimethylethane-1,2-diaminefor 1-methylpiperazine, and purified by the method described in Example23. ¹H NMR (400 MHz, DMSO-d₆/D₂O) δ 8.02 (d, J=2.4 Hz, 1H), 7.92 (dd,J=8.6, 2.4 Hz, 1H), 7.62 (d, J=7.7 Hz, 1H), 7.47 (t, J=7.9 Hz, 1H),7.44-7.42 (m, 1H), 7.31 (s, 1H), 7.29 (d, J=2.8 Hz, 1H), 7.22-7.18 (m,1H), 7.17 (d, J=8.7 Hz, 1H), 6.25 (d, J=2.9 Hz, 1H), 3.61 (t, J=6.1 Hz,2H), 3.55 (s, 3H), 3.30-3.27 (m, 2H), 3.22 (s, 3H), 2.85 (s, 6H). MS(APCI+) m/z 509.2 (M+H)⁺.

Example 343-[2-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-4-(methylsulfonyl)phenoxy]-N-[(2R)-tetrahydrofuran-2-ylmethyl]benzamide

The TFA salt of the title compound was prepared using the proceduredescribed for Example 22, substituting(R)-(tetrahydrofuran-2-yl)methanamine for 1-methylpiperazine, andpurified by the method described in Example 23. ¹H NMR (400 MHz,DMSO-d₆/D₂O) δ 8.00 (d, J=2.4 Hz, 1H), 7.90 (dd, J=8.7, 2.4 Hz, 1H),7.60 (d, J=7.7 Hz, 1H), 7.44 (dd, J=3.9, 1.9 Hz, 1H), 7.42 (d, J=7.9 Hz,1H), 7.32 (s, 1H), 7.29 (d, J=2.9 Hz, 1H), 7.16 (d, J=8.6 Hz, 1H),7.16-7.13 (m, 1H), 6.26 (d, J=2.8 Hz, 1H), 3.97 (p, J=6.4 Hz, 1H),3.80-3.69 (m, 1H), 3.63 (dd, J=14.4, 7.5 Hz, 1H), 3.55 (s, 3H), 3.31 (d,J=5.9 Hz, 2H), 3.22 (s, 3H), 1.98-1.85 (m, 1H), 1.81 (dt, J=15.0, 5.1Hz, 2H), 1.63-1.50 (m, 1H). MS (APCI+) m/z 522.2 (M+H)⁺.

Example 353-[2-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-4-(methylsulfonyl)phenoxy]-N-[2-(pyrrolidin-1-yl)ethyl]benzamide

The TFA salt of the title compound was prepared using the proceduredescribed for Example 22, substituting 2-(pyrrolidin-1-yl)ethanamine for1-methylpiperazine, and purified by the method described in Example 23.¹H NMR (400 MHz, DMSO-d₆/D₂O) δ 8.02 (d, J=2.4 Hz, 1H), 7.92 (dd, J=8.6,2.4 Hz, 1H), 7.62 (d, J=7.9 Hz, 1H), 7.51-7.45 (m, 1H), 7.44 (d, J=2.1Hz, 1H), 7.31 (s, 1H), 7.29 (d, J=2.9 Hz, 1H), 7.22-7.18 (m, 1H), 7.17(d, J=8.7 Hz, 1H), 6.25 (d, J=2.8 Hz, 1H), 3.60 (t, J=6.1 Hz, 3H), 3.55(s, 3H), 3.33 (t, J=6.1 Hz, 2H), 3.22 (s, 3H), 3.15 (s, 1H), 1.96 (s,4H). MS (APCI+) m/z 535.1 (M+H)⁺.

Example 36N-(3,5-difluorobenzyl)-3-[2-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-4-(methylsulfonyl)phenoxy]benzamide

The TFA salt of the title compound was prepared using the proceduredescribed for Example 22, substituting (3,5-difluorophenyl)methanaminefor 1-methylpiperazine, and purified by the method described in Example23. ¹H NMR (400 MHz, DMSO-d₆/D₂O) δ 8.00 (d, J=2.4 Hz, 1H), 7.91 (dd,J=8.7, 2.4 Hz, 1H), 7.65 (d, J=7.8 Hz, 1H), 7.49-7.47 (m, 1H), 7.48-7.42(m, 1H), 7.31 (s, 1H), 7.29 (t, J=3.2 Hz, 1H), 7.17 (dd, J=8.4, 3.6 Hz,2H), 6.95 (dd, J=14.9, 4.7 Hz, 3H), 6.25 (dd, J=9.3, 2.9 Hz, 1H), 4.46(s, 2H), 3.54 (s, 3H), 3.24-3.18 (m, 3H). MS (APCI+) m/z 564.1 (M+H)⁺.

Example 37N-(2,4-difluorobenzyl)-3-[2-(6-methyl-7-oxo-6,7-dihydro-H-pyrrolo[2,3-c]pyridin-4-yl)-4-(methylsulfonyl)phenoxy]benzamide

The TFA salt of the title compound was prepared using the proceduredescribed for Example 22, substituting (2,4-difluorophenyl)methanaminefor 1-methylpiperazine, and purified by the method described in Example23. ¹H NMR (400 MHz, DMSO-d₆/D₂O) δ 8.00 (d, J=2.4 Hz, 1H), 7.90 (dd,J=8.6, 2.4 Hz, 1H), 7.64 (d, J=7.7 Hz, 1H), 7.49-7.45 (m, 1H), 7.43 (d,J=7.8 Hz, 1H), 7.41-7.35 (m, 1H), 7.31 (s, 1H), 7.28 (d, J=2.8 Hz, 1H),7.16 (dd, J=8.3, 3.2 Hz, 2H), 7.10-7.03 (m, 1H), 6.99 (dd, J=9.8, 7.3Hz, 1H), 6.25 (d, J=2.8 Hz, 1H), 4.46 (s, 2H), 3.54 (s, 3H), 3.24-3.18(m, 3H). MS (APCI+) m/z 564.1 (M+H)⁺.

Example 38N-{3-[2-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-4-(methylsulfonyl)phenoxy]phenyl}-1-phenylmethanesulfonamideExample 38a 3-(2-bromo-4-(methylsulfonyl)phenoxy)aniline

A mixture of Example 21b (1.0 g, 3.95 mmol), 3-aminophenol (0.516 g,4.73 mmol), cesium carbonate (1.84 g, 5.65 mmol) and dimethylsulfoxide(16 mL) was heated at 120° C. in a sealed tube for 1 hour. The reactionmixture was cooled to ambient temperature and water (100 mL) was added.The mixture was extracted with ethyl acetate. The ethyl acetate layerwas washed with water, saturated aqueous sodium chloride, dried(anhydrous magnesium sulfate), filtered, and concentrated to afford 1.4g oil. The crude product was flash chromatographed (Biotage 50 g HP SnapCartridge, eluting with heptanes containing a gradient with ethylacetate, 10% to 75%) to provide the title compound (1.35 g, 3.94 mmol,100% yield)

Example 38b4-(2-(3-aminophenoxy)-5-(methylsulfonyl)phenyl)-6-methyl-H-pyrrol[2,3-c]pyridin-7(6H)-one

Using the procedure described for Example 1j and substituting Example38a for Example 1i provided the title compound.

Example 38cN-{3-[2-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-4-(methylsulfonyl)phenoxy]phenyl}-1-phenylmethanesulfonamide

A 4 mL vial was charged with Example 38b (24 mg, 0.061 mmol), phenylmethane sulfonyl chloride (14 mg, 0.07 mmol), and diisopropylethyl amine(30 μL, 0.18 mmol). The reaction mixture was allowed to stir at ambienttemperature overnight. The reaction mixture was concentrated and theresidue was purified by reverse phase HPLC (C18, CH₃CN/water (0.1% TFA),0-100% gradient) to provide the title compound. ¹H NMR (400 MHz,DMSO-d₆/D₂O) δ 8.03-7.91 (m, 2H), 7.41 (s, 1H), 7.37-7.25 (m, 5H),7.23-7.17 (m, 2H), 7.14 (d, J=8.6 Hz, 1H), 6.97 (d, J=7.1 Hz, 1H),6.80-6.74 (m, 2H), 6.27 (d, J=2.8 Hz, 1H), 4.42 (s, 2H), 3.58 (s, 3H),3.27 (s, 3H). MS (ESI+) m/z 564 (M+H)⁺.

Example 394-methoxy-N-{3-[2-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-4-(methylsulfonyl)phenoxy]phenyl}benzenesulfonamide

Example 39 was prepared according to the procedure used for thepreparation of Example 38c, substituting 4-methoxybenzene-1-sulfonylchloride for phenyl methane sulfonyl chloride to provide the titlecompound. ¹H NMR (400 MHz, DMSO-d₆/D₂O) δ 8.00 (d, J=2.4 Hz, 1H), 7.88(dd, J=8.7, 2.4 Hz, 1H), 7.75-7.54 (m, 2H), 7.39-7.28 (m, 2H), 7.28-7.12(m, 1H), 7.10-6.98 (m, 2H), 6.93 (d, J=8.7 Hz, 1H), 6.90-6.84 (m, 1H),6.72 (dd, J=8.7, 1.5 Hz, 2H), 6.20 (d, J=2.8 Hz, 1H), 3.83 (d, J=19.5Hz, 3H), 3.55 (s, 3H), 3.27 (s, 3H), 3.18 (s, 1H), 1.31-1.12 (m, 1H). MS(ESI+) m/z 580 (M+H)⁺.

Example 403-fluoro-N-{3-[2-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-4-(methylsulfonyl)phenoxy]phenyl}benzenesulfonamide

Example 40 was prepared according to the procedure used for thepreparation of Example 38c, substituting 3-fluorobenzene-1-sulfonylchloride for phenyl methane sulfonyl chloride. ¹H NMR (400 MHz,DMSO-d₆/D₂O) δ 7.99 (d, J=2.4 Hz, 1H), 7.88 (dd, J=8.6, 2.4 Hz, 1H),7.68-7.55 (m, 1H), 7.55-7.46 (m, 3H), 7.35 (s, 1H), 7.31 (d, J=2.8 Hz,1H), 7.27 (t, J=8.1 Hz, 2H), 6.98-6.86 (m, 2H), 6.77 (dd, J=8.1, 2.4 Hz,1H), 6.73 (t, J=2.2 Hz, 1H), 6.19 (d, J=2.8 Hz, 1H), 3.55 (s, 3H), 3.27(s, 3H). MS (ESI+) m/z 568 (M+H)⁺.

Example 414-fluoro-N-{3-[2-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-4-(methylsulfonyl)phenoxy]phenyl}benzenesulfonamide

Example 41 was prepared according to the procedure used for thepreparation of Example 38c, substituting 4-fluorobenzene-1-sulfonylchloride for phenyl methane sulfonyl chloride. ¹H NMR (400 MHz,DMSO-d₆/D₂O) δ 8.00 (d, J=2.4 Hz, 1H), 7.90 (dd, J=8.6, 2.4 Hz, 1H),7.78-7.70 (m, 2H), 7.42-7.34 (m, 3H), 7.32 (d, J=2.8 Hz, 1H), 7.26 (t,J=8.1 Hz, 1H), 6.96 (d, J=8.6 Hz, 1H), 6.87 (dd, J=8.0, 2.0 Hz, 1H),6.75 (dd, J=8.1, 2.4 Hz, 1H), 6.71 (t, J=2.2 Hz, 1H), 6.20 (d, J=2.8 Hz,1H), 3.56 (s, 3H), 3.27 (s, 3H). MS (ESI+) m/z 568 (M+H)⁺.

Example 423-methoxy-N-{3-[2-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-4-(methylsulfonyl)phenoxy]phenyl}benzenesulfonamide

Example 42 was prepared according to the procedure used for thepreparation of Example 38c, substituting 3-methoxybenzene-1-sulfonylchloride for phenyl methane sulfonyl chloride. ¹H NMR (400 MHz,DMSO-d₆/D₂O) δ 8.07-7.92 (m, 1H), 7.87 (dd, J=8.7, 2.4 Hz, 1H),7.49-7.44 (m, 1H), 7.34 (s, 1H), 7.31 (d, J=2.8 Hz, 1H), 7.25 (dd,J=8.3, 4.7 Hz, 2H), 7.22-7.19 (m, 2H), 7.05-6.86 (m, 2H), 6.75 (dd,J=4.1, 1.9 Hz, 2H), 6.33-6.15 (m, 1H), 3.54 (d, J=8.1 Hz, 3H), 3.28 (d,J=6.3 Hz, 3H). MS (ESI+) m/z 580 (M+H)⁺.

Example 43N-{3-[2-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-4-(methylsulfonyl)phenoxy]phenyl}-4-nitrobenzenesulfonamide

Example 43 was prepared according to the procedure used for thepreparation of Example 38c, substituting 4-nitrobenzene-1-sulfonylchloride for phenyl methane sulfonyl chloride. ¹H NMR (400 MHz,DMSO-d₆/D₂O) δ 8.52-8.31 (m, 2H), 8.00 (d, J=2.4 Hz, 1H), 7.96-7.91 (m,2H), 7.89 (dd, J=8.7, 2.4 Hz, 1H), 7.37 (s, 1H), 7.32 (d, J=2.8 Hz, 1H),7.28 (t, J=8.2 Hz, 1H), 6.99 (d, J=8.6 Hz, 1H), 6.90 (dd, J=8.0, 1.7 Hz,1H), 6.84-6.69 (m, 2H), 6.21 (d, J=2.8 Hz, 1H), 3.55 (s, 3H), 3.27 (s,3H). MS (ESI+) m/z 595 (M+H)⁺.

Example 444-acetyl-N-{3-[2-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-4-(methylsulfonyl)phenoxy]phenyl}benzenesulfonamide

Example 44 was prepared according to the procedure used for thepreparation of Example 38c, substituting 4-acetylbenzene-1-sulfonylchloride for phenyl methane sulfonyl chloride. ¹H NMR (400 MHz,DMSO-d₆/D₂O) δ 8.07 (d, J=8.5 Hz, 2H), 7.99 (d, J=2.4 Hz, 1H), 7.87 (dd,J=8.6, 2.4 Hz, 1H), 7.81 (d, J=8.4 Hz, 2H), 7.35 (s, 1H), 7.31 (d, J=2.8Hz, 1H), 7.26 (t, J=8.1 Hz, 1H), 6.95 (d, J=8.6 Hz, 1H), 6.89 (dd,J=8.0, 1.6 Hz, 1H), 6.81-6.68 (m, 2H), 6.20 (d, J=2.8 Hz, 1H), 3.55 (s,3H), 3.27 (s, 3H), 2.61 (s, 3H). MS (ESI+) m/z 592 (M+H)⁺.

Example 455-(dimethylamino)-N-{3-[2-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-4-(methylsulfonyl)phenoxy]phenyl}naphthalene-1-sulfonamide

Example 45 was prepared according to the procedure used for thepreparation of Example 38c, substituting 5-(dimethylamino)naphthalene-1-sulfonyl chloride for phenyl methane sulfonyl chloride. ¹HNMR (400 MHz, DMSO-d₆/D₂O) δ 8.46 (d, J=8.5 Hz, 1H), 8.31 (d, J=8.6 Hz,1H), 8.09 (dd, J=7.3, 1.2 Hz, 1H), 7.97 (d, J=2.4 Hz, 1H), 7.85 (dd,J=8.6, 2.4 Hz, 1H), 7.67-7.54 (m, 2H), 7.36-7.12 (m, 4H), 6.87-6.79 (m,2H), 6.64-6.59 (m, 2H), 6.10 (d, J=2.8 Hz, 1H), 3.48 (s, 3H), 3.28 (s,3H), 2.84 (s, 6H). MS (ESI+) m/z 643.1 (M+H)⁺.

Example 46N-{3-[2-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-4-(methylsulfonyl)phenoxy]phenyl}-4-(propan-2-yl)benzenesulfonamide

Example 46 was prepared according to the procedure used for thepreparation of Example 38c, substituting 4-isopropylbenzene-1-sulfonylchloride for phenyl methane sulfonyl chloride. ¹H NMR (400 MHz,DMSO-d₆/D₂O) δ 8.00 (d, J=2.4 Hz, 1H), 7.89 (dd, J=8.7, 2.4 Hz, 1H),7.60 (d, J=8.4 Hz, 2H), 7.40 (d, J=8.4 Hz, 2H), 7.32 (d, J=3.0 Hz, 2H),7.29-7.22 (m, 1H), 6.97 (d, J=8.6 Hz, 1H), 6.88 (dd, J=7.6, 1.3 Hz, 1H),6.74-6.68 (m, 2H), 6.19 (d, J=2.8 Hz, 1H), 3.55 (d, J=4.9 Hz, 3H), 3.27(s, 3H), 2.94 (hept, J=7.0 Hz, 1H), 1.17 (d, J=6.9 Hz, 6H). MS (ESI+)m/z 592.1 (M+H)⁺.

Example 472,4-difluoro-N-{3-[2-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-4-(methylsulfonyl)phenoxy]phenyl}benzenesulfonamide

Example 47 was prepared according to the procedure used for thepreparation of Example 38c, substituting 2,4-difluorobenzene-1-sulfonylchloride for phenyl methane sulfonyl chloride. ¹H NMR (400 MHz,DMSO-d₆/D₂O) δ 8.00 (d, J=2.4 Hz, 1H), 7.90 (dd, J=8.6, 2.4 Hz, 1H),7.81 (td, J=8.6, 6.2 Hz, 1H), 7.55-7.43 (m, 1H), 7.32 (dd, J=14.3, 11.5Hz, 2H), 7.29-7.17 (m, 2H), 6.97 (d, J=8.6 Hz, 1H), 6.89 (dd, J=8.1, 1.4Hz, 1H), 6.82-6.70 (m, 2H), 6.20 (d, J=2.8 Hz, 1H), 3.56 (s, 3H), 3.27(s, 3H). MS (ESI+) m/z 586 (M+H)⁺.

Example 483-(difluoromethoxy)-N-{3-[2-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-4-(methylsulfonyl)phenoxy]phenyl}benzenesulfonamide

Example 48 was prepared according to the procedure used for thepreparation of Example 38c, substituting 3-(difluoromethoxy)benzene-1-sulfonyl chloride for phenyl methane sulfonyl chloride. ¹H NMR(400 MHz, DMSO-d₆/D₂O) δ 7.99 (d, J=2.4 Hz, 1H), 7.87 (dd, J=8.6, 2.4Hz, 1H), 7.66-7.58 (m, 1H), 7.57-7.51 (m, 1H), 7.49-7.43 (m, 2H),7.43-7.19 (m, 4H), 6.92 (t, J=8.7 Hz, 2H), 6.81-6.72 (m, 2H), 6.20 (d,J=2.8 Hz, 1H), 3.55 (s, 3H), 3.26 (s, 3H). MS (ESI+) m/z 616 (M+H)⁺.

Example 49N-{3-[2-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-4-(methylsulfonyl)phenoxy]phenyl}cyclopropanesulfonamide

Example 49 was prepared according to the procedure used for thepreparation of Example 38c, substituting cyclopropane sulfonyl chloridefor phenyl methane sulfonyl chloride. ¹H NMR (400 MHz, DMSO-d₆/D₂O) δ8.00 (d, J=2.4 Hz, 1H), 7.93 (dd, J=8.6, 2.4 Hz, 1H), 7.42-7.32 (m, 3H),7.32 (d, J=4.7 Hz, 2H), 7.16 (d, J=8.6 Hz, 1H), 7.02 (dd, J=8.0, 2.1 Hz,1H), 6.88 (t, J=2.2 Hz, 1H), 6.80 (dd, J=8.1, 2.4 Hz, 1H), 6.26 (d,J=2.8 Hz, 1H), 3.57 (s, 3H), 3.26 (s, 3H), 0.97-0.83 (m, 4H). MS (ESI+)m/z 514 (M+H)⁺.

Example 503-methyl-N-{3-[2-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-4-(methylsulfonyl)phenoxy]phenyl}benzenesulfonamide

Example 50 was prepared according to the procedure used for thepreparation of Example 38c, substituting 3-methylbenzene-1-sulfonylchloride for phenyl methane sulfonyl chloride. ¹H NMR (400 MHz,DMSO-d₆/D₂O) δ 7.99 (d, J=2.4 Hz, 1H), 7.87 (dd, J=8.6, 2.4 Hz, 1H),7.53 (s, 1H), 7.50-7.39 (m, 3H), 7.31 (d, J=2.8 Hz, 1H), 7.29-7.21 (m,1H), 6.96-6.85 (m, 2H), 6.76-6.71 (m, 2H), 6.19 (d, J=2.8 Hz, 1H), 3.55(s, 3H), 3.27 (s, 3H), 2.31 (s, 3H). MS (ESI+) m/z 564 (M+H)⁺.

Example 51N-{3-[2-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-4-(methylsulfonyl)phenoxy]phenyl}-3-nitrobenzenesulfonamide

Example 51 was prepared according to the procedure used for thepreparation of Example 38c, substituting 3-nitrobenzene-1-sulfonylchloride for phenyl methane sulfonyl chloride. ¹H NMR (400 MHz,DMSO-d₆/D₂O) δ 8.50-8.38 (m, 2H), 8.09-8.03 (m, 1H), 7.99 (d, J=2.4 Hz,1H), 7.90-7.82 (m, 2H), 7.36 (s, 1H), 7.30 (d, J=2.8 Hz, 2H), 7.29 (t,J=8.1 Hz, 2H), 6.97-6.88 (m, 2H), 6.80 (dd, J=8.1, 2.4 Hz, 1H), 6.76 (t,J=2.2 Hz, 1H), 6.19 (d, J=2.8 Hz, 1H), 3.55 (s, 3H), 3.27 (s, 3H). MS(ESI+) m/z 595 (M+H)⁺.

Example 524-fluoro-2-methyl-N-{3-[2-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-4-(methylsulfonyl)phenoxy]phenyl}benzenesulfonamide

Example 52 was prepared according to the procedure used for thepreparation of Example 38c, substituting4-fluoro-2-methylbenzene-1-sulfonyl chloride for phenyl methane sulfonylchloride. ¹H NMR (400 MHz, DMSO-d₆/D₂O) δ 8.00 (d, J=2.4 Hz, 1H), 7.90(dd, J=8.6, 2.4 Hz, 1H), 7.81 (dd, J=8.8, 5.7 Hz, 1H), 7.35-7.26 (m,3H), 7.28-7.23 (m, 1H), 7.22 (d, J=8.1 Hz, 1H), 7.15 (td, J=8.5, 2.7 Hz,1H), 6.97 (d, J=8.6 Hz, 1H), 6.84 (dd, J=8.1, 2.0 Hz, 1H), 6.69 (dd,J=8.1, 2.4 Hz, 1H), 6.65 (t, J=2.2 Hz, 1H), 6.18 (d, J=2.8 Hz, 1H), 3.55(s, 3H), 3.28 (s, 3H). MS (ESI+) m/z 582 (M+H)⁺.

Example 533,4-dimethoxy-N-{3-[2-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-4-(methylsulfonyl)phenoxy]phenyl}benzenesulfonamide

Example 53 was prepared according to the procedure used for thepreparation of Example 38c, substituting 3,4-dimethoxybenzene-1-sulfonylchloride for phenyl methane sulfonyl chloride. ¹H NMR (400 MHz,DMSO-d₆/D₂O) δ 7.99 (d, J=2.4 Hz, 1H), 7.85 (dd, J=8.7, 2.4 Hz, 1H),7.33 (d, J=10.9 Hz, 1H), 7.30 (dd, J=12.0, 5.6 Hz, 1H), 7.27-7.18 (m,2H), 7.03 (d, J=8.5 Hz, 1H), 6.95-6.90 (m, 1H), 6.87 (d, J=8.6 Hz, 1H),6.75 (dd, J=8.8, 1.4 Hz, 2H), 6.19 (d, J=2.8 Hz, 1H), 3.81 (s, 3H), 3.68(s, 3H), 3.55 (s, 3H), 3.23 (d, J=35.1 Hz, 3H). MS (ESI+) m/z 610(M+H)⁺.

Example 54N-{3-[2-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-4-(methylsulfonyl)phenoxy]phenyl}-4-(methylsulfonyl)benzenesulfonamide

Example 54 was prepared according to the procedure used for thepreparation of Example 38c, substituting 4-(methylsulfonyl)benzene-1-sulfonyl chloride for phenyl methane sulfonyl chloride. ¹H NMR(400 MHz, DMSO-d₆/D₂O) δ 8.13-8.08 (m, 2H), 8.01-7.85 (m, 4H), 7.36 (s,1H), 7.32 (d, J=2.8 Hz, 1H), 7.28 (t, J=8.1 Hz, 2H), 6.96 (d, J=8.6 Hz,1H), 6.90 (dd, J=8.0, 2.1 Hz, 1H), 6.78 (dd, J=8.1, 2.4 Hz, 1H), 6.74(t, J=2.2 Hz, 1H), 6.21 (d, J=2.8 Hz, 1H), 3.55 (s, 3H), 3.26 (d, J=1.4Hz, 6H). MS (ESI+) m/z 627.9 (M+H)⁺.

Example 552-cyano-N-{3-[2-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-4-(methylsulfonyl)phenoxy]phenyl}benzenesulfonamide

Example 55 was prepared according to the procedure used for thepreparation of Example 38c, substituting 2-cyanobenzene-1-sulfonylchloride for phenyl methane sulfonyl chloride. ¹H NMR (400 MHz,DMSO-d₆/D₂O) δ 8.06 (dd, J=7.3, 1.7 Hz, 1H), 8.00-7.94 (m, 2H),7.90-7.81 (m, 3H), 7.34 (s, 1H), 7.33-7.28 (m, 1H), 7.26 (d, J=8.2 Hz,1H), 7.01 (d, J=8.6 Hz, 1H), 6.87 (dd, J=8.0, 1.8 Hz, 1H), 6.78 (dd,J=8.1, 2.2 Hz, 1H), 6.71 (t, J=2.2 Hz, 1H), 6.19 (d, J=2.8 Hz, 1H), 3.55(s, 3H), 3.27 (s, 3H). MS (ESI+) m/z 575.0 (M+H)⁺.

Example 564-cyano-N-{3-[2-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-4-(methylsulfonyl)phenoxy]phenyl}benzenesulfonamide

Example 56 was prepared according to the procedure used for thepreparation of Example 38c, substituting 4-cyanobenzene-1-sulfonylchloride for phenyl methane sulfonyl chloride. ¹H NMR (400 MHz,DMSO-d₆/D₂O) δ 8.08-7.98 (m, 3H), 7.91 (dt, J=8.2, 4.1 Hz, 1H),7.89-7.80 (m, 2H), 7.36 (s, 1H), 7.33 (d, J=2.8 Hz, 1H), 7.27 (t, J=8.2Hz, 1H), 6.99 (d, J=8.6 Hz, 1H), 6.86 (dd, J=8.0, 1.7 Hz, 1H), 6.78 (dd,J=8.1, 2.2 Hz, 1H), 6.72 (t, J=2.2 Hz, 1H), 6.21 (d, J=2.8 Hz, 1H), 3.55(s, 3H), 3.27 (s, 3H). MS (ESI+) m/z 575.0 (M+H)⁺.

Example 573-cyano-N-{3-[2-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-4-(methylsulfonyl)phenoxy]phenyl}benzenesulfonamide

Example 57 was prepared according to the procedure used for thepreparation of Example 38c, substituting 3-cyanobenzene-1-sulfonylchloride for phenyl methane sulfonyl chloride. ¹H NMR (400 MHz,DMSO-d₆/D₂O) δ 8.34-8.05 (m, 2H), 8.04-7.84 (m, 3H), 7.83-7.70 (m, 1H),7.41-7.20 (m, 3H), 7.00-6.85 (m, 2H), 6.85-6.70 (m, 2H), 6.21 (dd,J=8.0, 2.8 Hz, 1H), 3.55 (d, J=3.9 Hz, 3H), 3.28 (d, J=10.6 Hz, 3H). MS(ESI+) m/z 575 (M+H)⁺.

Example 582-chloro-4-fluoro-N-{3-[2-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-4-(methylsulfonyl)phenoxy]phenyl}benzenesulfonamide

Example 58 was prepared according to the procedure used for thepreparation of Example 38c, substituting2-chloro-4-fluorobenzene-1-sulfonyl chloride for phenyl methane sulfonylchloride. ¹H NMR (400 MHz, DMSO-d₆/D₂O) δ 8.03-7.96 (m, 2H), 7.89 (dd,J=8.6, 2.4 Hz, 1H), 7.66 (dd, J=8.5, 2.5 Hz, 1H), 7.47-7.27 (m, 3H),7.25 (t, J=8.0 Hz, 1H), 6.96 (d, J=8.6 Hz, 1H), 6.91-6.85 (m, 1H),6.75-6.68 (m, 2H), 6.19 (d, J=2.8 Hz, 1H), 3.55 (s, 3H), 3.27 (s, 3H).MS (ESI+) m/z 602 (M+H)⁺.

Example 591-methyl-N-{3-[2-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-4-(methylsulfonyl)phenoxy]phenyl}-1H-imidazole-4-sulfonamide

Example 59 was prepared according to the procedure used for thepreparation of Example 38c, substituting1-methyl-1H-imidazole-4-sulfonyl chloride for phenyl methane sulfonylchloride. ¹H NMR (500 MHz, DMSO-d₆/D₂O) δ 7.95 (d, J=2.4 Hz, 1H), 7.86(dd, J=8.7, 2.4 Hz, 1H), 7.74-7.62 (m, 2H), 7.34 (s, 1H), 7.29 (d, J=2.8Hz, 1H), 7.21 (t, J=8.2 Hz, 1H), 6.96 (d, J=8.7 Hz, 1H), 6.91 (dd,J=8.2, 1.3 Hz, 1H), 6.81 (t, J=2.1 Hz, 1H), 6.67 (dd, J=8.2, 1.8 Hz,1H), 6.19 (d, J=2.8 Hz, 1H), 3.60 (s, 3H), 3.53 (s, 3H), 3.22 (s, 3H).MS (ESI+) m/z 554.1 (M+H)⁺.

Example 603-[({3-[2-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-4-(methylsulfonyl)phenoxy]phenyl}amino)methyl]benzonitrile

A 4 mL vial was charged with a solution of Example 38b (21 mg, 0.05mmol) in 1M solution of ammonium acetate/acetic acid buffer in methanol(pH=4) (1.0 mL), a solution of 3-formylbenzonitrile (10 mg, 0.08 mmol)dissolved in the above buffer solution (0.3 mL), followed by 60 mg ofMP-Cyanoborohydride resin (0.88 mmol/g). The resulting reaction mixturewas shaken at 40° C. for overnight. The reaction mixture was filteredand purification by reverse phase HPLC (C18, CH₃CN/water (0.1% TFA),0-100% gradient) provided the TFA salt of the title compound (12 mg, 36%yield). ¹H NMR (400 MHz, DMSO-d₆/D₂O) δ 7.94 (d, J=2.4 Hz, 1H), 7.83(dd, J=8.7, 2.4 Hz, 1H), 7.73 (s, 1H), 7.67 (dd, J=17.7, 7.8 Hz, 2H),7.53 (t, J=7.7 Hz, 1H), 7.36 (s, 1H), 7.30 (d, J=2.8 Hz, 1H), 7.09 (t,J=8.1 Hz, 1H), 6.97 (d, J=8.7 Hz, 1H), 6.44 (dd, J=8.1, 1.9 Hz, 1H),6.28-6.23 (m, 1H), 6.22 (t, J=2.5 Hz, 2H), 4.31 (s, 2H), 3.57 (d, J=4.7Hz, 3H), 3.26-3.20 (m, 3H). MS (ESI+) m/z 525 (M+H)⁺.

Example 614-[({3-[2-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-4-(methylsulfonyl)phenoxy]phenyl}amino)methyl]benzonitrile

Using the procedure described for Example 60 and substituting4-formylbenzonitrile for 3-formylbenzonitrile provided the TFA salt ofthe title compound. ¹H NMR (400 MHz, DMSO-d₆/D₂O) δ 7.93 (d, J=2.4 Hz,1H), 7.84 (dd, J=8.7, 2.4 Hz, 1H), 7.76 (d, J=8.3 Hz, 2H), 7.48 (d,J=8.3 Hz, 2H), 7.35 (s, 1H), 7.30 (d, J=2.8 Hz, 1H), 7.07 (t, J=8.1 Hz,1H), 7.00 (d, J=8.7 Hz, 1H), 6.40 (d, J=10.0 Hz, 1H), 6.24 (d, J=7.9 Hz,1H), 6.20 (d, J=2.8 Hz, 1H), 6.17 (d, J=2.1 Hz, 1H), 4.33 (s, 2H), 3.57(s, 3H), 3.23 (s, 3H). MS (ESI+) m/z 525 (M+H)⁺.

Example 624-[2-{3-[(4-fluorobenzyl)amino]phenoxy}-5-(methylsulfonyl)phenyl]-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one

Using the procedure described for Example 60 and substituting4-fluorobenzaldehyde for 3-formylbenzonitrile provided the TFA salt ofthe title compound. ¹H NMR (400 MHz, DMSO-d₆/D₂O) δ 7.94 (d, J=2.4 Hz,1H), 7.84 (dd, J=8.7, 2.4 Hz, 1H), 7.36-7.30 (m, 4H), 7.15-7.05 (m, 3H),7.00 (d, J=8.7 Hz, 1H), 6.44 (dd, J=8.1, 1.8 Hz, 1H), 6.23 (dq, J=6.9,2.1 Hz, 3H), 4.21 (s, 2H), 3.57 (s, 3H), 3.23 (s, 3H); MS (ESI+) m/z 518(M+H)⁺.

Example 634-{2-[(2,2-difluorocyclopropyl)methoxy]-5-(ethylsulfonyl)phenyl}-2-[3-(dimethylamino)prop-1-yn-1-yl]-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-oneExample 63a 4-bromo-2-iodo-7-methoxy-1-tosyl-1H-pyrrolo[2,3-c]pyridine

To a solution of n-BuLi (2.5 M, 36 mL, 90 mmol) in anhydroustetrahydrofuran (200 mL) was added diisopropylamine (7.33 g, 72.4 mmol)dropwise at -70° C. and the reaction mixture was then stirred at fromabout −70° C. to about −50° C. for 45 minutes. To the solution ofExample 1c (23.0 g, 60.3 mmol) in anhydrous tetrahydrofuran (400 mL) wasadded the above lithium diispropylamide solution dropwise at -70° C. andthe mixture was stirred for 1.5 hours. Then a solution of diiodine (35.2g, 139 mmol) in anhydrous tetrahydrofuran (300 mL) was added dropwise tothe above mixture at -70° C. The reaction mixture was stirred foranother 3 hours and poured into aqueous Na₂S₂O₃ solution. The suspensionwas filtered. The filter cake was washed with dichloromethane and thendried to give the title compound (16 g, 31.5 mmol, 52.3% yield).

Example 63b 4-bromo-2-iodo-1-tosyl-1H-pyrrolo[2,3-c]pyridin-7(6H)-one

Example 63b was prepared according to the procedure used for thepreparation of Example 1d, substituting Example 63a for Example 1c.

Example 63c

Example 63c was prepared according to the procedure used for thepreparation of Example 1e, substituting Example 63b for Example 1d.

Example 63d4-bromo-2-(3-(dimethylamino)prop-1-yn-1-yl)-6-methyl-1-tosyl-1H-pyrrolo[2,3-c]pyridin-7(6H)-one

To a round bottom flask equipped with a reflux condenser were addedExample 63c (500 mg, 0.986 mmol), N,N-dimethylprop-2-yn-1-amine (164 mg,1.972 mmol), PdCl₂(PPh₃)₂ (69.2 mg, 0.099 mmol), CuI (37.6 mg, 0.197mmol), triethylamine (2.75 mL, 19.72 mmol) and dimethylformamide (10mL). The suspension was heated at 70° C. for 2 hours. The reactionmixture was cooled to ambient temperature, filtered through Celite, andwashed with ethyl acetate several times. The residue was partitionedbetween water (100 mL) and ethyl acetate (100 mL). The organic layer wasseparated and the aqueous layer was extracted with ethyl acetate again(50 mL twice). The combined organic layers were dried over anhydroussodium sulfate, filtered, and concentrated. The residue was purified bya flash chromatography (silica gel, ethyl acetate/petroleum ether, 1/10to 1/3 gradient) to afford the title compound (350 mg, 49% yield).

Example 63e2-(5-(ethylsulfonyl)-2-fluorophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane

4,4,4′,4′,5,5,5′,5′-Octamethyl-2,2′-bi(1,3,2-dioxaborolane) (13.31 g,52.4 mmol), Example 16i (10 g, 37.4 mmol), potassium acetate (7.35 g,74.9 mmol), and PdCl₂(dppf) (0.822 g, 1.123 mmol) were combined indioxane (100 mL) and DMSO (3 mL). The reaction mixture was sparged withN2 for 30 minutes and heated at 90° C. under N2 for 16 hours. Aftercooling, the reaction mixture was partitioned between ethyl acetate andwater and filtered through a plug of Celite to remove elementalpalladium. The layers were separated and the organic layer was washedwith saturated aqueous sodium chloride, dried over anhydrous sodiumsulfate, treated with mercaptopropyl silica gel for 15 minutes,filtered, and concentrated. The crude product was recrystallized inheptane/ethyl acetate (4:1) to afford the title compound as ambercrystals (10 g, 30.0 mmol, 80% yield).

Example 63f2-(3-(dimethylamino)prop-1-yn-1-yl)-4-(5-(ethylsulfonyl)-2-fluorophenyl)-6-methyl-1-tosyl-1H-pyrrolo[2,3-c]pyridin-7(6H)-one

To a 10 mL microwave tube was added Example 63d (10 mg, 0.022 mmol),Example 63e (10.19 mg, 0.032 mmol), PdCl₂(dppf) dichloromethane adduct(0.950 mg, 1.30 μmol), Na₂CO₃ (6.88 mg, 0.065 mmol), dioxane (1 mL) andwater (0.250 mL). The reaction mixture was heated to 130° C. in amicrowave reactor for 50 minutes. The reaction mixture was filteredthrough Celite and washed with ethyl acetate several times. The solventwas evaporated and the residue was partitioned between water (20 mL) andethyl acetate (20 mL). The organic layer was separated and the aqueouslayer was extracted with ethyl acetate again (15 mL twice). The combinedorganic layers were dried under anhydrous sodium sulfate, filtered, andconcentrated. The crude product was used directly without purification.

Example 63g4-{2-[(2,2-difluorocyclopropyl)methoxy]-5-(ethylsulfonyl)phenyl}-2-[3-(dimethylamino)prop-1-yn-1-yl]-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one

NaH (35.1 mg, 0.878 mmol) was added to Example 63f (100 mg, 0.176 mmol)in dimethylformamide (10 mL), and the mixture was stirred for 10minutes. (2,2-Difluorocyclopropyl)methanol (56.9 mg, 0.527 mmol) wasadded, and the mixture was stirred for 3 hours at ambient temperature.The residue was partitioned between water (10 mL) and ethyl acetate (20mL). The organic layer was separated, and the aqueous layer wasextracted with additional ethyl acetate twice (20 mL). The combinedorganic layers were washed with saturated aqueous sodium bicarbonate (10mL), followed by saturated aqueous sodium chloride (100 mL), dried overanhydrous magnesium sulfate, filtered, and concentrated. The crudematerial was purified by reverse phase Prep HPLC (C18, 30-40%acetonitrile in 0.1% NH₄HCO₃/water) to afford the title compound (25 mg,28% yield). ¹H NMR (400 MHz, CDCl₃) δ 10.91 (s, 1H), 7.96-7.84 (m, 2H),7.13-7.04 (m, 2H), 6.37 (d, J=1.0 Hz, 1H), 4.23-4.08 (m, 2H), 3.71 (s,3H), 3.52 (s, 2H), 3.14 (q, J=7.4 Hz, 2H), 2.38 (s, 6H), 2.05-1.97 (m,1H), 1.53 (dd, J=8.0, 4.6 Hz, 1H), 1.31 (t, J=7.4 Hz, 3H), 1.28-1.18 (m,1H). MS (ESI+) m/z 504.2 (M+H)⁺.

Example 644-[2-{3-[(2-methoxyethyl)amino]phenoxy}-5-(methylsulfonyl)phenyl]-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one

Using the procedure described for Example 60 and substituting2-methoxyacetaldehyde for 3-formylbenzonitrile provided the TFA salt ofthe title compound. ¹H NMR (400 MHz, DMSO-d₆/D₂O) δ 7.95 (d, J=2.4 Hz,1H), 7.87 (dd, J=8.7, 2.4 Hz, 1H), 7.40 (s, 1H), 7.33 (d, J=2.8 Hz, 1H),7.10-7.01 (m, 2H), 6.48 (dd, J=8.2, 1.9 Hz, 1H), 6.33 (t, J=2.2 Hz, 1H),6.29 (d, J=2.8 Hz, 1H), 6.19 (dd, J=7.9, 2.1 Hz, 1H), 3.59 (s, 3H), 3.22(d, J=8.7 Hz, 3H), 2.76 (s, 2H), 0.91 (s, 9H); MS (ESI+) m/z 468 (M+H)⁺.

Example 656-methyl-4-[5-(methylsulfonyl)-2-{3-[(tetrahydrofuran-2-ylmethyl)amino]phenoxy}phenyl]-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one

Using the procedure described for Example 60 and substitutingtetrahydrofuran-2-carbaldehyde for 3-formylbenzonitrile provided thetitle compound. ¹H NMR (400 MHz, DMSO-d₆/D₂O) δ 7.95 (d, J=2.4 Hz, 1H),7.88 (dd, J=8.7, 2.4 Hz, 1H), 7.40 (s, 1H), 7.33 (d, J=2.8 Hz, 1H),7.14-7.04 (m, 2H), 6.49 (dd, J=8.1, 1.9 Hz, 1H), 6.35 (t, J=2.1 Hz, 1H),6.28 (dd, J=8.3, 2.4 Hz, 2H), 3.92 (dd, J=11.7, 6.7 Hz, 1H), 3.75 (dd,J=11.8, 9.5 Hz, 54H), 3.62 (dd, J=14.3, 7.6 Hz, 1H), 3.58 (s, 3H), 3.24(s, 3H), 3.04 (qd, J=13.2, 5.7 Hz, 2H), 2.02-1.87 (m, 1H), 1.87-1.73 (m,2H), 1.54 (dt, J=15.1, 6.9 Hz, 1H); MS (ESI+) m/z 494 (M+H)⁺.

Example 664-[2-{3-[(3-methoxybenzyl)amino]phenoxy}-5-(methylsulfonyl)phenyl]-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one

Using the procedure described for Example 60 and substituting3-methoxybenzaldehyde for 3-formylbenzonitrile provided the TFA salt ofthe title compound. ¹H NMR (400 MHz, DMSO-d₆/D₂O) δ 7.93 (d, J=2.4 Hz,1H), 7.83 (dd, J=8.7, 2.4 Hz, 1H), 7.35 (s, 1H), 7.30 (d, J=2.8 Hz, 1H),7.23 (t, J=8.1 Hz, 1H), 7.08 (t, J=8.3 Hz, 1H), 6.98 (d, J=8.7 Hz, 1H),6.87 (d, J=6.9 Hz, 2H), 6.81-6.76 (m, 1H), 6.47-6.42 (m, 1H), 6.22 (dd,J=7.4, 4.7 Hz, 3H), 4.20 (s, 2H), 3.70 (s, 3H), 3.56 (s, 3H), 3.23 (s,3H); MS (ESI+) m/z 530 (M+H)⁺.

Example 674-[2-{3-[(2-fluorobenzyl)amino]phenoxy}-5-(methylsulfonyl)phenyl]-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one

Using the procedure described for Example 60 and substituting2-fluorobenzaldehyde for 3 formylbenzonitrile provided the TFA salt ofthe title compound. ¹H NMR (400 MHz, DMSO-d₆/D₂O) δ 7.94 (d, J=2.4 Hz,1H), 7.84 (dd, J=8.7, 2.4 Hz, 1H), 7.38-7.26 (m, 4H), 7.18-7.06 (m, 3H),7.01 (d, J=8.7 Hz, 1H), 6.47-6.42 (m, 1H), 6.24 (dd, J=10.4, 2.4 Hz,3H), 4.26 (s, 2H), 3.56 (s, 3H), 3.24 (d, J=6.8 Hz, 3H); MS (ESI+) m/z518 (M+H)⁺.

Example 684-[2-{3-[(3-fluorobenzyl)amino]phenoxy}-5-(methylsulfonyl)phenyl]-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one

Using the procedure described for Example 60 and substituting3-fluorobenzaldehyde for 3-formylbenzonitrile provided the TFA salt ofthe title compound. ¹H NMR (400 MHz, DMSO-d₆/D₂O) δ 7.93 (d, J=2.4 Hz,1H), 7.83 (dd, J=8.7, 2.4 Hz, 1H), 7.38-7.32 (m, 2H), 7.29 (d, J=2.8 Hz,1H), 7.09 (ddd, J=25.6, 16.8, 8.0 Hz, 4H), 6.98 (d, J=8.7 Hz, 1H),6.46-6.41 (m, 1H), 6.22 (dd, J=7.8, 5.4 Hz, 3H), 4.26 (s, 2H), 3.56 (s,3H), 3.23 (s, 3H); MS (ESI+) m/z 518 (M+H)⁺.

Example 696-methyl-4-[5-(methylsulfonyl)-2-(3-{[3-(trifluoromethoxy)benzyl]amino}phenoxy)phenyl]-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one

Using the procedure described for Example 60 and substituting3-(trifluoromethoxy)benzaldehyde for 3-formylbenzonitrile provided theTFA salt of the title compound. ¹H NMR (400 MHz, DMSO-d₆/D₂O) δ 7.93 (d,J=2.4 Hz, 1H), 7.81 (dd, J=8.7, 2.4 Hz, 1H), 7.45 (t, J=7.9 Hz, 1H),7.38-7.32 (m, 2H), 7.29 (d, J=2.8 Hz, 1H), 7.26 (s, 1H), 7.20 (d, J=8.2Hz, 1H), 7.09 (t, J=8.1 Hz, 1H), 6.95 (d, J=8.7 Hz, 1H), 6.45 (dd,J=8.2, 1.9 Hz, 1H), 6.27-6.23 (m, 1H), 6.22 (t, J=2.9 Hz, 2H), 4.30 (s,2H), 3.56 (s, 3H), 3.23 (s, 3H); MS (ESI+) m/z 584 (M+H)⁺.

Example 704-[2-{3-[(2,4-dimethylbenzyl)amino]phenoxy}-5-(methylsulfonyl)phenyl]-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one

Using the procedure described for Example 60 and substituting2,4-dimethylbenzaldehyde for 3-formylbenzonitrile provided the TFA saltof the title compound. ¹H NMR (400 MHz, DMSO-d₆/D₂O) δ 7.93 (d, J=2.4Hz, 1H), 7.85 (dd, J=8.7, 2.4 Hz, 1H), 7.34 (s, 1H), 7.30 (d, J=2.8 Hz,1H), 7.11-7.05 (m, 2H), 7.03 (d, J=8.7 Hz, 1H), 6.97 (s, 1H), 6.92 (d,J=7.7 Hz, 1H), 6.43 (dd, J=8.1, 1.9 Hz, 1H), 6.23 (dd, J=8.2, 2.4 Hz,2H), 6.19 (t, J=2.1 Hz, 1H), 4.11 (s, 2H), 3.56 (s, 3H), 3.23 (s, 3H),2.23 (d, J=3.3 Hz, 6H); MS (ESI+) m/z 528 (M+H)⁺.

Example 712-[({3-[2-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-4-(methylsulfonyl)phenoxy]phenyl}amino)methyl]benzonitrile

Using the procedure described for Example 60 and substituting2-formylbenzonitrile for 3-formylbenzonitrile provided the TFA salt ofthe title compound. ¹H NMR (400 MHz, DMSO-d₆/D₂O) δ 8.26 (d, J=7.9 Hz,1H), 8.02 (d, J=2.4 Hz, 1H), 7.93 (dd, J=8.7, 2.4 Hz, 1H), 7.87 (t,J=7.7 Hz, 1H), 7.80 (d, J=7.6 Hz, 1H), 7.72 (t, J=7.5 Hz, 1H), 7.65 (t,J=8.1 Hz, 1H), 7.48-7.44 (m, 1H), 7.43-7.41 (m, 2H), 7.34 (dd, J=5.7,2.9 Hz, 2H), 7.29 (dd, J=8.3, 2.1 Hz, 1H), 6.32 (d, J=2.8 Hz, 1H), 5.19(s, 2H), 3.58 (s, 3H), 3.26 (s, 3H); MS (ESI+) m/z 525 (M+H)⁺.

Example 724-[2-{3-[(2-chloro-4-fluorobenzyl)amino]phenoxy}-5-(methylsulfonyl)phenyl]-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one

Using the procedure described for Example 60 and substituting2-chloro-4-fluorobenzaldehyde for 3-formylbenzonitrile provided the TFAsalt of the title compound. ¹H NMR (400 MHz, DMSO-d₆/D₂O) δ 7.95 (t,J=5.9 Hz, 1H), 7.85 (dd, J=8.7, 2.4 Hz, 1H), 7.41-7.35 (m, 2H), 7.34 (s,1H), 7.30 (d, J=2.8 Hz, 1H), 7.17 (td, J=8.5, 2.6 Hz, 1H), 7.09 (t,J=8.1 Hz, 1H), 7.02 (d, J=8.7 Hz, 1H), 6.40 (dd, J=8.1, 1.9 Hz, 1H),6.31-6.16 (m, 2H), 6.14 (t, J=2.2 Hz, 1H), 4.25 (s, 2H), 3.56 (s, 3H),3.24 (s, 3H); MS (ESI+) m/z 552 (M+H)⁺.

Example 734-[2-{3-[(3,5-difluorobenzyl)amino]phenoxy}-5-(methylsulfonyl)phenyl]-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one

Using the procedure described for Example 60 and substituting3,5-difluorobenzaldehyde for 3-formylbenzonitrile provided the TFA saltof the title compound. ¹H NMR (400 MHz, DMSO-d₆/D₂O) δ 7.94 (d, J=2.4Hz, 1H), 7.83 (dd, J=8.7, 2.4 Hz, 1H), 7.36 (s, 1H), 7.29 (d, J=2.8 Hz,1H), 7.10 (t, J=8.1 Hz, 1H), 7.02 (ddd, J=19.8, 11.0, 5.5 Hz, 4H), 6.44(dd, J=8.1, 2.0 Hz, 1H), 6.31-6.17 (m, 3H), 4.28 (s, 2H), 3.57 (s, 3H),3.23 (s, 3H); MS (ESI+) m/z 536 (M+H)⁺.

Example 744-{2-[3-({4-[3-(dimethylamino)propoxy]benzyl}amino)phenoxy]-5-(methylsulfonyl)phenyl}-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one

Using the procedure described for Example 60 and substituting4-(3-(dimethylamino)propoxy)benzaldehyde for 3-formylbenzonitrileprovided the TFA salt of the title compound. ¹H NMR (400 MHz,DMSO-d₆/D₂O) δ 7.94 (d, J=2.4 Hz, 1H), 7.83 (dd, J=8.7, 2.4 Hz, 1H),7.35 (s, 1H), 7.31 (d, J=2.8 Hz, 1H), 7.22 (d, J=8.6 Hz, 2H), 7.15-7.04(m, 2H), 6.97 (d, J=8.7 Hz, 1H), 6.88-6.84 (m, 2H), 6.45 (dd, J=8.2, 1.8Hz, 1H), 6.23-6.17 (m, 2H), 4.16 (s, 2H), 4.01 (t, J=5.9 Hz, 2H), 3.56(s, 3H), 3.24 (s, 3H), 3.23-3.17 (m, 2H), 2.82 (s, 6H), 2.12-2.05 (m,2H); MS (ESI+) m/z 601 (M+H)⁺.

Example 754-[2-(3-{[3-(dimethylamino)benzyl]amino}phenoxy)-5-(methylsulfonyl)phenyl]-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one

Using the procedure described for Example 60 and substituting3-(dimethylamino)benzaldehyde for 3-formylbenzonitrile provided the TFAsalt of the title compound. ¹H NMR (400 MHz, DMSO-d₆/D₂O) δ 7.94 (d,J=2.4 Hz, 1H), 7.84 (dd, J=8.7, 2.4 Hz, 1H), 7.39-7.33 (m, 2H), 7.30 (d,J=2.8 Hz, 1H), 7.21 (s, 1H), 7.11 (dd, J=16.8, 8.7 Hz, 3H), 6.99 (d,J=8.7 Hz, 1H), 6.49-6.41 (m, 1H), 6.27 (dd, J=10.8, 2.2 Hz, 2H), 6.22(d, J=2.8 Hz, 1H), 4.25 (s, 2H), 3.57 (s, 3H), 3.23 (s, 3H), 3.02 (s,6H); MS (ESI+) m/z 543 (M+H)⁺

Example 764-[2-{3-[(2,3-dihydro-1,4-benzodioxin-6-ylmethyl)amino]phenoxy}-5-(methylsulfonyl)phenyl]-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one

Using the procedure described for Example 60 and substituting2,3-dihydrobenzo[b][1,4]dioxine-6-carbaldehyde for 3-formylbenzonitrileprovided the TFA salt of the title compound. ¹H NMR (400 MHz,DMSO-d₆/D₂O) δ 7.93 (d, J=2.4 Hz, 1H), 7.84 (dd, J=8.7, 2.4 Hz, 1H),7.35 (s, 1H), 7.31 (d, J=2.8 Hz, 1H), 7.08 (dd, J=9.7, 6.2 Hz, 1H), 6.99(d, J=8.7 Hz, 1H), 6.79-6.72 (m, 3H), 6.44 (d, J=7.2 Hz, 1H), 6.22 (dd,J=4.2, 2.0 Hz, 3H), 4.19 (s, 4H), 4.10 (s, 2H), 3.57 (s, 3H), 3.23 (s,3H); MS (ESI+) m/z 558 (M+H)⁺.

Example 776-methyl-4-[5-(methylsulfonyl)-2-{3-[(tetrahydrofuran-3-ylmethyl)amino]phenoxy}phenyl]-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one

Using the procedure described for Example 60 and substitutingtetrahydrofuran-3-carbaldehyde for 3-formylbenzonitrile provided the TFAsalt of the title compound. ¹H NMR (400 MHz, DMSO-d₆/D₂O) δ 7.96 (d,J=2.4 Hz, 1H), 7.88 (dd, J=8.7, 2.4 Hz, 1H), 7.40 (s, 1H), 7.34 (d,J=2.8 Hz, 1H), 7.15-7.10 (m, 1H), 7.08 (d, J=8.7 Hz, 1H), 6.48-6.44 (m,1H), 6.27 (dd, J=11.2, 2.4 Hz, 3H), 3.73-3.69 (m, 2H), 3.66-3.60 (m,1H), 3.58 (s, 3H), 3.41 (dd, J=8.5, 5.6 Hz, 1H), 3.24 (s, 3H), 2.94 (d,J=7.3 Hz, 2H), 2.46-2.34 (m, 1H), 1.97 (dtd, J=13.3, 7.9, 5.5 Hz, 1H),1.56 (dt, J=12.7, 6.8 Hz, 1H); MS (ESI+) m/z 494 (M+H)⁺.

Example 78N-{4-[({3-[2-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-4-(methylsulfonyl)phenoxy]phenyl}amino)methyl]phenyl}acetamide

Using the procedure described for Example 60 and substitutingN-(4-formylphenyl)acetamide for 3-formylbenzonitrile provided the TFAsalt of the title compound. ¹H NMR (400 MHz, DMSO-d₆/D₂O) δ 7.93 (d,J=2.4 Hz, 1H), 7.83 (dd, J=8.7, 2.4 Hz, 1H), 7.49 (d, J=8.5 Hz, 2H),7.36 (s, 1H), 7.30 (d, J=2.8 Hz, 1H), 7.22 (d, J=8.5 Hz, 2H), 7.13-7.08(m, 1H), 6.96 (d, J=8.7 Hz, 1H), 6.50 (dd, J=8.2, 1.6 Hz, 1H), 6.31-6.24(m, 2H), 6.27 (dd, J=6.5, 2.0 Hz, 1H), 6.22 (d, J=2.8 Hz, 1H), 4.19 (s,2H), 3.57 (s, 3H), 3.23 (s, 3H), 2.04 (s, 3H); MS (ESI+) m/z 557 (M+H)⁺.

Example 794-[2-{3-[(4-methoxybenzyl)amino]phenoxy}-5-(methylsulfonyl)phenyl]-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one

Using the procedure described for Example 60 and substituting4-methoxybenzaldehyde for 3-formylbenzonitrile provided the TFA salt ofthe title compound. ¹H NMR (400 MHz, DMSO-d₆/D₂O) δ 7.92 (t, J=8.2 Hz,1H), 7.84 (dd, J=8.7, 2.4 Hz, 1H), 7.35 (s, 1H), 7.31 (d, J=2.8 Hz, 1H),7.21 (d, J=8.6 Hz, 2H), 7.08 (t, J=8.0 Hz, 1H), 6.99 (d, J=8.7 Hz, 1H),6.87 (d, J=8.6 Hz, 2H), 6.51-6.40 (m, 1H), 6.26-6.17 (m, 3H), 4.15 (s,2H), 3.72 (s, 3H), 3.56 (s, 3H), 3.23 (s, 3H); MS (ESI+) m/z 530 (M+H)⁺.

Example 804-[2-{3-[(cyclopropylmethyl)amino]phenoxy}-5-(methylsulfonyl)phenyl]-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one

Using the procedure described for Example 60 and substitutingcyclopropanecarbaldehyde for 3-formylbenzonitrile provided the TFA saltof the title compound. ¹H NMR (400 MHz, DMSO-d₆/D₂O) δ 7.97 (d, J=2.4Hz, 1H), 7.90 (dd, J=8.7, 2.4 Hz, 1H), 7.40 (d, J=2.1 Hz, 1H), 7.33 (d,J=2.8 Hz, 1H), 7.21 (t, J=7.9 Hz, 1H), 7.12 (d, J=8.7 Hz, 1H), 6.66-6.61(m, 1H), 6.52-6.40 (m, 2H), 6.28 (d, J=2.9 Hz, 1H), 3.58 (s, 3H), 3.25(s, 3H), 2.91 (d, J=6.8 Hz, 2H), 0.95 (td, J=7.6, 3.7 Hz, 1H), 0.49-0.43(m, 2H), 0.21-0.17 (m, 2H); MS (ESI+) m/z 464 (M+H)⁺.

Example 814-[2-{3-[(2-cyclopentylethyl)amino]phenoxy}-5-(methylsulfonyl)phenyl]-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one

Using the procedure described for Example 60 and substitutingcyclopentylacetaldehyde for 3-formylbenzonitrile provided the TFA saltof the title compound. ¹H NMR (400 MHz, DMSO-d₆/D₂O) δ 7.97 (d, J=2.4Hz, 1H), 7.89 (dd, J=8.7, 2.4 Hz, 1H), 7.40 (s, 1H), 7.33 (d, J=2.8 Hz,1H), 7.15 (t, J=8.4 Hz, 1H), 7.09 (d, J=8.7 Hz, 1H), 6.50 (d, J=7.5 Hz,1H), 6.34-6.31 (m, 2H), 6.28 (d, J=2.8 Hz, 1H), 3.58 (s, 3H), 3.24 (s,3H), 3.04-2.92 (m, 2H), 1.86-1.67 (m, 3H), 1.61-1.41 (m, 6H), 1.07 (td,J=14.9, 7.2 Hz, 2H); MS (ESI+) m/z 506 (M+H)⁺.

Example 824-[2-{4-chloro-2-[3-(morpholin-4-yl)prop-1-yn-1-yl]phenoxy}-5-(ethylsulfonyl)phenyl]-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-oneExample 82a4-(5-(ethylsulfonyl)-2-fluorophenyl)-6-methyl-1-tosyl-1H-pyrrolo[2,3-c]pyridin-7(6H)-one

Example 82a was prepared according to the procedure used for thepreparation of Example 16j, substituting Example 1f for Example 16f.

Example 82b4-(2-(4-chloro-2-iodophenoxy)-5-(ethylsulfonyl)phenyl)-6-methyl-H-pyrrolo[2,3-c]pyridin-7(6H)-one

A mixture of Example 82a (0.51 g, 1.047 mmol), 4-chloro-2-iodophenol(0.293 g, 1.151 mmol), and cesium carbonate (0.409 g, 1.256 mmol) indimethylsulfoxide (5 mL) was heated at 95° C. overnight. After coolingto ambient temperature, the reaction mixture was partitioned betweenwater and ethyl acetate. The organic layer was separated, and theaqueous layer was extracted with additional ethyl acetate twice. Thecombined organic layers were washed with saturated aqueous sodiumchloride, dried over anhydrous magnesium sulfate, filtered, andconcentrated. The residue was purified by flash column chromatography(silica gel, 1:1 ethyl acetate/hexanes) to afford the title compound(0.22 g, 0.387 mmol, 37% yield).

Example 82c4-[2-{4-chloro-2-[3-(morpholin-4-yl)prop-1-yn-1-yl]phenoxy}-5-(ethylsulfonyl)phenyl]-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one

A mixture of Example 82b (0.100 g, 0.176 mmol),4-(prop-2-yn-1-yl)morpholine (0.044 g, 0.35 mmol), copper(I) iodide(6.70 mg, 0.035 mmol), triethylamine (0.503 mL, 3.52 mmol), andbis(triphenylphosphine)palladium(II) chloride (0.012 g, 0.018 mmol) indimethylformamide (1 mL) was heated at 80° C. for 2 hours. After coolingto ambient temperature, the reaction mixture was partitioned betweenwater and ethyl acetate. The aqueous layer was extracted with additionalethyl acetate twice. The combined organic layers were washed withsaturated aqueous sodium chloride, dried over anhydrous magnesiumsulfate, filtered, and concentrated. The residue was purified by reversephase Prep HPLC (C18, 10-100% acetonitrile in 0.1% TFA/water) to affordthe title compound as TFA salt (0.075 g, 0.110 mmol, 62.7% yield). ¹HNMR (400 MHz, DMSO-d₆) δ 12.12 (s, 1H), 7.98 (d, J=2.44 Hz, 1H), 7.84(dd, J=8.54, 2.44 Hz, 1H), 7.73 (d, J=2.44 Hz, 1H), 7.53 (dd, J=8.85,2.75 Hz, 1H), 7.44 (s, 1H), 7.33 (t, J=2.75 Hz, 1H), 7.23 (d, J=8.85 Hz,1H), 7.07 (d, J=8.54 Hz, 1H), 6.31 (t, J=2.29 Hz, 1H), 4.09 (br s, 2H),3.62 (br s, 4H), 3.57 (s, 3H), 3.32-3.38 (m, 2H), 2.92 (br s, 4H), 1.15(t, J=7.32 Hz, 3H). MS (ESI+) m/z 566.1 (M+H)⁺.

Example 834-[2-{4-chloro-2-[3-(morpholin-4-yl)propyl]phenoxy}-5-(ethylsulfonyl)phenyl]-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one

Example 82c (60 mg, 0.106 mmol) and tetrahydrofuran (10 mL) were addedto 5% Pt/C (about 50% water) (30 mg, 0.063 mmol) in a 50 mL pressurebottle. The reaction mixture was stirred at 30 psi of hydrogen andambient temperature for 2 hours. The mixture was filtered through anylon membrane and concentrated. The residue was purified by reversephase Prep HPLC (C18, 10-100% acetonitrile in 0.1% TFA/water) to affordthe title compound as TFA salt (0.045 g, 0.066 mmol, 62.1% yield). ¹HNMR (400 MHz, DMSO-d₆) δ 12.15 (s, 1H), 9.64 (s, 1H), 7.96 (d, J=2.44Hz, 1H), 7.86 (dd, J=8.7, 2.29 Hz, 1H), 7.45 (d, J=2.44 Hz, 1H), 7.42(s, 1H), 7.31-7.35 (m, 1H), 7.09 (d, J=5.49 Hz, 1H), 7.06 (d, J=8.54 Hz,1H), 6.25 (t, J=2.29 Hz, 1H), 3.91-3.94 (m, 2H), 3.57 (s, 3H), 3.32-3.38(m, 2H), 3.21-3.24 (m, 2H), 2.90 (br s, 4H), 2.46-2.52 (m, 4H),1.71-1.79 (m, 2H), 1.16 (t, J=7.32 Hz, 3H). MS (ESI+) m/z 570.2 (M+H)⁺.

Example 846-methyl-4-[5-(methylsulfonyl)-2-{[1-(phenylsulfonyl)piperidin-4-yl]amino}phenyl]-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-oneExample 84a tert-butyl4-((2-bromo-4-(methylsulfonyl)phenyl)amino)piperidine-1-carboxylate

A solution of Example 21b (2.71 g, 10.71 mmol),N,N-diisopropylethylamine (2.15 mL, 12.31 mmol), and tert-butyl4-aminopiperidine-1-carboxylate (2.43 g, 11.78 mmol) indimethylsulfoxide (20 mL) was stirred at 100° C. for 4 hours. To thecooled mixture was added dilute ammonium chloride solution and extractedtwice with diethylether. The combined organic layers were dried withanhydrous magnesium sulfate, filtered, and concentrated. The residue waspurified by chromatography (silica gel, 40-66% ethyl acetate in heptane)to afford 3.21 g (62%) of the title compound.

Example 84b tert-butyl4-{[2-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-4-(methylsulfonyl)phenyl]amino}piperidine-1-carboxylate

Example 84a (3.19 g, 7.36 mmol), Example 1f (3.31 g, 7.73 mmol),tetrakis(triphenylphosphine)palladium (0) (0.851 g, 0.736 mmol), andcesium fluoride (3.35 g, 22.08 mmol) were combined and sparged withargon for 10 minutes, followed by the addition of dimethoxyethane (70mL) and methanol (35 mL), and bubbled argon through the mixture for 15minutes. Reaction mixture was stirred at 75° C. for 2 hours. To thecooled reaction mixture was added 5N sodium hydroxide aqueous solution(100 mL) and stirred for 2 hours at ambient temperature. To theresulting mixture was added dilute ammonium chloride solution andextracted twice with ethyl acetate. The combined organic layers weredried with anhydrous magnesium sulfate, filtered, and concentrated. Theresidue was purified by chromatography (silica gel, 80% ethyl acetate inheptane) to afford 1.80 g (49%) of the title compound.

Example 84c6-methyl-4-[5-(methylsulfonyl)-2-(piperidin-4-ylamino)phenyl]-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one

A solution of Example 84b (1.53 g, 3.06 mmol) in dichloromethane (14 mL)was stirred at ambient temperature. To this solution was added excesstrifluoroacetic acid (2 mL) and stirred 4 hours at ambient temperature.The mixture was neutralized slowly with sodium carbonate solution untilpH was about 10, and extracted twice with dichloromethane. The combinedorganic layers were dried with anhydrous magnesium sulfate, filtered,and concentrated. The solid residue was triturated with warm ethylacetate, filtered, and dried to afford 1.01 g (82%) of title compound.

Example 84d6-methyl-4-[5-(methylsulfonyl)-2-{[1-(phenylsulfonyl)piperidin-4-yl]amino}phenyl]-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one

A solution of Example 84c (0.039 g, 0.097 mmol) and 4-methylmorpholine(0.015 mL, 0.136 mmol) in dimethylformamide (4.0 mL) was stirred atambient temperature. To this solution was added benzenesulfonyl chloride(0.014 mL, 0.107 mmol) and stirred for 1.5 hours at ambient temperature.Dilute aqueous sodium chloride solution was added to the reactionmixture and extracted twice with ethyl acetate. The combined organiclayers were dried with anhydrous magnesium sulfate, filtered, andconcentrated. The solid residue was triturated with ethyl acetate,filtered, and dried to afford 0.043 g (82%) of the title compound. ¹HNMR (400 MHz, DMSO-d₆) δ 12.11 (s, 1H), 7.77-7.70 (m, 3H), 7.66 (dd,J=10.1, 4.9 Hz, 2H), 7.60 (dd, J=8.7, 2.3 Hz, 1H), 7.49 (d, J=2.3 Hz,1H), 7.23 (dd, J=5.5, 2.8 Hz, 2H), 6.88 (d, J=9.0 Hz, 1H), 5.95 (t,J=2.3 Hz, 1H), 5.05 (d, J=8.1 Hz, 1H), 3.58-3.42 (m, 6H), 3.09 (s, 3H),2.43 (dd, J=11.5, 9.9 Hz, 2H), 1.89 (d, J=10.7 Hz, 2H), 1.40 (td,J=14.3, 3.8 Hz, 2H). MS (ESI+) m/z 541.1 (M+H)⁺.

Example 854-[2-({1-[(dimethylamino)acetyl]piperidin-4-yl}amino)-5-(methylsulfonyl)phenyl]-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one

A solution of Example 84c (0.028 g, 0.070 mmol) and 4-methylmorpholine(0.009 mL, 0.083 mmol) in dimethylformamide (4.0 mL) was stirred atambient temperature. To this solution was added 2-(dimethylamino)acetylchloride, hydrochloride (0.012 g, 0.076 mmol) and stirred for 2 hours atambient temperature. Dilute aqueous sodium chloride and dilute sodiumbicarbonate solution was added to reaction mixture until pH was about 9,and extracted twice with ethyl acetate. The combined organic layers weredried with anhydrous magnesium sulfate, filtered, and concentrated. Theresidue was triturated with ethyl acetate, filtered, and dried to afford0.019 g (56%) of the title compound. ¹H NMR (400 MHz, DMSO-d₆) δ 12.11(s, 1H), 7.67 (dd, J=8.7, 2.3 Hz, 1H), 7.52 (d, J=2.3 Hz, 1H), 7.27 (dd,J=7.1, 4.4 Hz, 2H), 6.95 (d, J=9.0 Hz, 1H), 6.00 (s, 1H), 5.07 (d, J=8.1Hz, 1H), 4.22 (d, J=13.0 Hz, 1H), 3.95 (d, J=13.4 Hz, 1H), 3.77-3.63 (m,1H), 3.55 (s, 3H), 3.16-2.90 (m, 6H), 2.70 (t, J=11.5 Hz, 1H), 2.13 (s,6H), 1.92-1.78 (m, 2H), 1.28 (dd, J=20.4, 10.9 Hz, 1H), 1.14 (dd,J=20.5, 10.8 Hz, 1H). MS (ESI+) m/z 486.2 (M+H)⁺.

Example 866-methyl-4-[2-({1-[3-(methylsulfanyl)propyl]piperidin-4-yl}amino)-5-(methylsulfonyl)phenyl]-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one

A 4 mL vial was charged with Example 84c (25 mg, 0.063 mmol),3-(methylthio)propanal (10 mg, 0.095 mmol), in a buffer solution of 1Msodium acetate/acetic acid in methanol with pH 4 (1.5 mL), followed bythe addition of Silica-cyanoborohydride (150 mg, loading 0.89 mmol/g).The reaction mixture was allowed to stir at ambient temperatureovernight. The reaction mixture was concentrated and the residue waspurified by reverse phase HPLC (C18, CH₃CN/water (0.1% TFA), 0-100%gradient) to afford the TFA salt of the title compound. ¹H NMR (400 MHz,PYRIDINE-d₅) δ 13.66 (s, 1H), 8.17 (dd, J=8.7, 2.3 Hz, 1H), 8.09 (d,J=2.3 Hz, 1H), 7.59 (d, J=2.7 Hz, 1H), 7.03 (d, J=8.9 Hz, 1H), 6.96 (s,1H), 6.41-6.31 (m, 1H), 3.71 (t, J=19.0 Hz, 1H), 3.49 (s, 3H), 3.31 (s,3H), 3.14 (s, 2H), 2.74 (d, J=6.9 Hz, 2H), 2.53 (d, J=24.4 Hz, 2H), 2.47(t, J=7.1 Hz, 2H), 2.35-2.10 (m, 2H), 1.99 (s, 3H), 1.96-1.66 (m, 4H) MS(ESI+) m/z 489.1 (M+H)⁺.

Example 87N-{4-[(4-{[2-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-4-(methylsulfonyl)phenyl]amino}piperidin-1-yl)methyl]phenyl}acetamide

The TFA salt of Example 87 was prepared according to the procedure usedfor the preparation of Example 86, substituting N-(4-formylphenyl)acetamide for 3-(methylthio)propanal. ¹H NMR (400 MHz, PYRIDINE-d₅) δ13.64 (s, 1H), 10.85 (s, 1H), 8.17 (dd, J=8.7, 2.3 Hz, 1H), 8.06 (t,J=13.4 Hz, 1H), 7.99 (d, J=8.4 Hz, 2H), 7.59 (d, J=2.7 Hz, 1H), 7.44 (d,J=8.5 Hz, 2H), 7.03 (d, J=8.9 Hz, 1H), 6.95 (s, 1H), 6.35 (t, J=2.3 Hz,1H), 5.76 (d, J=7.3 Hz, 1H), 3.81 (d, J=1.7 Hz, 2H), 3.69 (s, 1H), 3.48(s, 3H), 3.30 (s, 3H), 3.11 (d, J=11.9 Hz, 2H), 2.52 (t, J=10.2 Hz, 2H),2.18 (s, 3H), 2.12 (d, J=12.5 Hz, 2H), 1.85 (d, J=10.8 Hz, 2H). MS(ESI+) m/z 548.2 (M+H)⁺.

Example 886-methyl-4-[5-(methylsulfonyl)-2-{[1-(3,4,5-trimethoxybenzyl)piperidin-4-yl]amino}phenyl]-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one

The TFA salt of Example 88 was prepared according to the procedure usedfor the preparation of Example 86, substituting3,4,5-trimethoxybenzaldehyde for 3-(methylthio)propanal. ¹H NMR (400MHz, PYRIDINE-d₅) δ 13.65 (s, 1H), 8.17 (dd, J=8.7, 2.3 Hz, 1H), 8.09(d, J=2.3 Hz, 1H), 7.59 (dd, J=4.7, 2.0 Hz, 1H), 7.04 (d, J=8.9 Hz, 2H),6.95 (s, 1H), 6.89 (s, 2H), 6.41-6.31 (m, 1H), 5.82 (d, J=7.1 Hz, 1H),3.91 (d, J=5.3 Hz, 5H), 3.76 (s, 6H), 3.48 (s, 3H), 3.31 (s, 3H), 3.19(t, J=20.3 Hz, 2H), 2.66 (t, J=10.5 Hz, 2H), 2.18 (d, J=12.5 Hz, 2H),1.94 (d, J=10.1 Hz, 2H) MS (ESI+) m/z 581.1 (M+H)⁺.

Example 896-methyl-4-[5-(methylsulfonyl)-2-{[1-(thiophen-2-ylmethyl)piperidin-4-yl]amino}phenyl]-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one

The TFA salt of Example 89 was prepared according to the procedure usedfor the preparation of Example 86, substituting thiophene-2-carbaldehydefor 3-(methylthio)propanal. ¹H NMR (400 MHz, PYRIDINE-d₅) δ 13.68 (s,1H), 8.17 (dd, J=8.7, 2.3 Hz, 1H), 8.08 (d, J=2.3 Hz, 1H), 7.40 (dd,J=4.9, 1.3 Hz, 1H), 7.02 (td, J=5.6, 3.3 Hz, 3H), 6.96 (s, 1H), 6.35 (t,J=2.4 Hz, 1H), 5.58 (d, J=7.4 Hz, 1H), 3.82 (d, J=2.8 Hz, 2H), 3.72-3.60(m, 1H), 3.54 (d, J=31.4 Hz, 4H), 3.30 (s, 3H), 3.00 (t, J=39.6 Hz, 2H),2.28 (t, J=10.6 Hz, 2H), 1.93 (t, J=62.3 Hz, 2H), 1.67 (d, J=10.7 Hz,2H) MS (ESI+) m/z 497.2 (M+H)⁺.

Example 904-{2-[(1-{4-[3-(dimethylamino)propoxy]benzyl}piperidin-4-yl)amino]-5-(methylsulfonyl)phenyl}-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one

The TFA salt of Example 90 was prepared according to the procedure usedfor the preparation of Example 86, substituting4-(3-(dimethylamino)propoxy)benzaldehyde for 3-(methylthio)propanal. ¹HNMR (400 MHz, PYRIDINE-d₅) δ 13.65 (s, 1H), 8.17 (dd, J=8.7, 2.3 Hz,1H), 8.09 (d, J=2.3 Hz, 1H), 7.59 (dd, J=4.7, 2.0 Hz, 1H), 7.04 (d,J=8.9 Hz, 2H), 6.95 (s, 1H), 6.89 (s, 2H), 6.41-6.31 (m, 1H), 5.82 (d,J=7.1 Hz, 1H), 3.91 (d, J=5.3 Hz, 5H), 3.76 (s, 6H), 3.48 (s, 3H), 3.31(s, 3H), 3.19 (t, J=20.3 Hz, 2H), 2.66 (t, J=10.5 Hz, 2H), 2.18 (d,J=12.5 Hz, 2H), 1.94 (d, J=10.1 Hz, 2H). MS (ESI+) m/z 592.2 (M+H)⁺.

Example 916-methyl-4-[2-({1-[(methylsulfanyl)acetyl]piperidin-4-yl}amino)-5-(methylsulfonyl)phenyl]-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one

A 4 mL vial was charged with 2-(methylthio) acetic acid (11 mg, 0.10mmol), O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate (40 mg, 0.10 mmol) followed by the addition ofdiisopropyl ethyl amine (61 μL, 0.35 mmol) and Example 84c (28 mg, 0.07mmol) in 1.5 mL of dimethyl acetamide. The reaction mixture was allowedto stir at ambient temperature overnight. The reaction mixture wasconcentrated and the residue was purified by reverse phase HPLC (C18,CH₃CN/water (0.1% TFA), 0-100% gradient) to afford the TFA salt of thetitle compound. ¹H NMR (400 MHz, DMSO-d₆/D₂O) δ 7.70 (dd, J=8.8, 2.4 Hz,1H), 7.54 (d, J=2.4 Hz, 1H), 7.29 (d, J=2.8 Hz, 1H), 7.18 (s, 1H), 6.97(d, J=8.9 Hz, 1H), 6.02 (d, J=2.8 Hz, 1H), 3.78-3.64 (m, 2H), 3.57 (s,3H), 3.31 (d, J=8.5 Hz, 2H), 3.20 (s, 2H), 3.07 (s, 3H), 2.07 (s, 3H),2.01-1.85 (m, 2H), 1.28 (s, 2H). MS (ESI+) m/z 489.1 (M+H)⁺.

Example 926-methyl-4-[5-(methylsulfonyl)-2-({1-[3-(2,3,4-trimethoxyphenyl)propanoyl]piperidin-4-yl}amino)phenyl]-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one

The TFA salt of Example 92 was prepared according to the procedure usedfor the preparation of Example 91, substituting3-(2,3,4-trimethoxyphenyl)propanoic acid for 2-(methylthio) acetic acid.¹H NMR (400 MHz, DMSO-d₆/D₂O) δ 7.70 (dd, J=8.7, 2.4 Hz, 1H), 7.53 (d,J=2.3 Hz, 1H), 7.29 (d, J=2.8 Hz, 1H), 7.18 (s, 1H), 6.96 (d, J=8.9 Hz,1H), 6.81 (d, J=8.5 Hz, 1H), 6.64 (d, J=8.5 Hz, 1H), 6.01 (d, J=2.8 Hz,1H), 3.76 (d, J=3.7 Hz, 3H), 3.72 (d, J=6.2 Hz, 6H), 3.68 (dd, J=9.0,5.0 Hz, 2H), 3.57 (s, 3H), 3.07 (s, 3H), 2.76-2.66 (m, 2H), 2.47 (d,J=7.2 Hz, 2H), 1.94-1.82 (m, 2H), 1.17 (td, J=14.1, 4.2 Hz, 2H). MS(ESI+) m/z 623.2 (M+H)⁺.

Example 931-[(4-{[2-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-4-(methylsulfonyl)phenyl]amino}piperidin-1-yl)carbonyl]cyclopropanecarboxamide

The TFA salt of Example 93 was prepared according to the procedure usedfor the preparation of Example 91, substituting1-carbamoylcyclopropanecarboxylic acid for 2-(methylthio) acetic acid.¹H NMR (400 MHz, DMSO-d₆/D₂O) δ 7.70 (dd, J=8.7, 2.4 Hz, 1H), 7.54 (d,J=2.4 Hz, 1H), 7.40-7.25 (m, 1H), 7.18 (s, 1H), 6.97 (d, J=8.9 Hz, 1H),6.02 (d, J=2.8 Hz, 1H), 3.96 (d, J=10.8 Hz, 2H), 3.82-3.63 (m, 1H), 3.58(s, 3H), 3.07 (s, 3H), 3.02 (d, J=12.1 Hz, 2H), 1.96-1.84 (m, 2H), 1.29(td, J=14.3, 4.1 Hz, 2H), 1.20 (dd, J=7.2, 4.1 Hz, 2H), 1.04 (dd, J=7.2,4.1 Hz, 2H). MS (ESI+) m/z 512.1 (M+H)⁺.

Example 944-[2-({1-[(4-methoxycyclohexyl)carbonyl]piperidin-4-yl}amino)-5-(methylsulfonyl)phenyl]-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one

The TFA salt of Example 94 was prepared according to the procedure usedfor the preparation of Example 91, substituting4-methoxycyclohexanecarboxylic acid for 2-(methylthio) acetic acid. ¹HNMR (400 MHz, DMSO-d₆/D₂O) δ 7.70 (dd, J=8.7, 2.4 Hz, 1H), 7.53 (d,J=2.4 Hz, 1H), 7.29 (d, J=2.8 Hz, 1H), 7.17 (s, 1H), 6.96 (d, J=8.9 Hz,1H), 6.01 (d, J=2.8 Hz, 1H), 3.98 (s, 3H), 3.70 (qd, J=9.7, 4.6 Hz, 1H),3.57 (s, 3H), 3.36 (d, J=6.3 Hz, 1H), 3.20 (d, J=2.0 Hz, 3H), 3.07 (s,3H), 2.96 (t, J=23.7 Hz, 2H), 2.57 (ddd, J=14.4, 7.2, 3.7 Hz, 2H), 1.85(ddd, J=13.1, 10.4, 3.2 Hz, 4H), 1.68-1.53 (m, 2H), 1.49-1.29 (m, 4H),1.21 (dd, J=20.4, 9.8 Hz, 2H). MS (ESI+) m/z 541.2 (M+H)⁺.

Example 954-[2-{[1-(methoxyacetyl)piperidin-4-yl]amino}-5-(methylsulfonyl)phenyl]-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one

The TFA salt of Example 95 was prepared according to the procedure usedfor the preparation of Example 91, substituting 2-methoxyacetic acid for2-(methylthio) acetic acid. ¹H NMR (400 MHz, DMSO-d₆/D₂O) δ 7.70 (dd,J=8.8, 2.4 Hz, 1H), 7.54 (d, J=2.3 Hz, 1H), 7.44-7.25 (m, 1H), 7.18 (s,1H), 6.97 (d, J=8.9 Hz, 1H), 6.02 (d, J=2.8 Hz, 1H), 3.99 (d, J=12.9 Hz,3H), 3.92 (s, 1H), 3.70 (ddt, J=18.1, 12.2, 6.2 Hz, 2H), 3.57 (s, 3H),3.27 (s, 3H), 3.07 (s, 3H), 2.94 (d, J=31.1 Hz, 2H), 2.01-1.84 (m, 2H),1.24 (dd, J=20.7, 9.9 Hz, 2H). MS (ESI+) m/z 473.2 (M+H)⁺.

Example 966-methyl-4-[2-({1-[(4-methylpiperazin-1-yl)acetyl]piperidin-4-yl}amino)-5-(methylsulfonyl)phenyl]-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one

The TFA salt of Example 96 was prepared according to the procedure usedfor the preparation of Example 91, substituting2-(4-methylpiperazin-1-yl) acetic acid for 2-(methylthio) acetic acid.¹H NMR (400 MHz, DMSO-d₆/D₂O) δ 7.71 (dd, J=8.7, 2.3 Hz, 1H), 7.55 (d,J=2.3 Hz, 1H), 7.30 (d, J=2.8 Hz, 1H), 7.19 (s, 1H), 6.97 (d, J=8.7 Hz,1H), 6.03 (d, J=2.8 Hz, 1H), 3.96-3.59 (m, 2H), 3.58 (s, 3H), 3.54 (bs,2H), 3.25-3.19 (m, 4H), 3.08 (s, 3H), 3.06-2.85 (m, 5H), 2.77 (s, 3H),1.99-1.87 (m, 2H), 1.41-1.19 (m, 2H). MS (ESI+) m/z 541.2 (M+H)⁺.

Example 976-methyl-4-[5-(methylsulfonyl)-2-{[1-(pyrrolidin-1-ylacetyl)piperidin-4-yl]amino}phenyl]-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one

The TFA salt of Example 97 was prepared according to the procedure usedfor the preparation of Example 91, substituting 2-(pyrrolidin-1-yl)acetic acid for 2-(methylthio) acetic acid. ¹H NMR (400 MHz,DMSO-d₆/D₂O) δ 7.72 (dd, J=8.7, 2.3 Hz, 1H), 7.55 (d, J=2.3 Hz, 1H),7.30 (d, J=2.8 Hz, 1H), 7.19 (s, 1H), 6.99 (d, J=8.7 Hz, 1H), 6.03 (d,J=2.8 Hz, 1H), 4.23 (s, 2H), 3.84-3.61 (m, 2H), 3.58 (s, 3H), 3.56-3.38(m, 2H), 3.08 (s, 4H), 2.14-1.88 (m, 6H), 1.39-1.20 (m, 2H). MS (ESI+)m/z 512.2 (M+H)⁺.

Example 984-[2-({1-[(2-methoxyethoxy)acetyl]piperidin-4-yl}amino)-5-(methylsulfonyl)phenyl]-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one

The TFA salt of Example 98 was prepared according to the procedure usedfor the preparation of Example 91, substituting 2-(2-methoxyethoxy)acetic acid for 2-(methylthio) acetic acid. ¹H NMR (400 MHz,DMSO-d₆/D₂O) δ 7.70 (dd, J=8.7, 2.4 Hz, 1H), 7.54 (d, J=2.3 Hz, 1H),7.29 (d, J=2.8 Hz, 1H), 7.18 (s, 1H), 6.97 (d, J=8.9 Hz, 1H), 6.01 (d,J=2.9 Hz, 1H), 4.08 (s, 2H), 3.94 (d, J=26.7 Hz, 2H), 3.78-3.64 (m, 1H),3.57 (s, 3H), 3.56-3.49 (m, 2H), 3.49-3.41 (m, 2H), 3.21 (d, J=8.8 Hz,3H), 3.07 (s, 3H), 2.94 (d, J=33.7 Hz, 2H), 1.91 (dt, J=8.1, 7.4 Hz,2H), 1.23 (dd, J=15.3, 8.3 Hz, 2H). MS (ESI+) m/z 517.1 (M+H)⁺.

Example 996-methyl-4-[5-(methylsulfonyl)-2-({1-[3-(morpholin-4-yl)propanoyl]piperidin-4-yl}amino)phenyl]-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one

The TFA salt of Example 99 was prepared according to the procedure usedfor the preparation of Example 91, substituting 3-morpholinopropanoicacid for 2-(methylthio) acetic acid. ¹H NMR (400 MHz, DMSO-d₆/D₂O) δ7.72 (dd, J=8.8, 2.4 Hz, 1H), 7.55 (d, J=2.3 Hz, 1H), 7.30 (d, J=2.8 Hz,1H), 7.19 (s, 1H), 6.98 (d, J=8.9 Hz, 1H), 6.02 (d, J=2.8 Hz, 1H), 3.83(s, 4H), 3.75 (td, J=10.1, 5.0 Hz, 2H), 3.58 (s, 3H), 3.34 (t, J=6.9 Hz,2H), 3.27-3.22 (m, 4H), 3.08 (s, 3H), 2.78 (dd, J=23.9, 16.9 Hz, 2H),2.02-1.83 (m, 2H), 1.25 (s, 2H). MS (ESI+) m/z 542.2 (M+H)⁺.

Example 1006-methyl-4-[2-({1-[(4-methylphenyl)acetyl]piperidin-4-yl}amino)-5-(methylsulfonyl)phenyl]-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one

Example 100 was prepared according to the procedure used for thepreparation of Example 91, substituting 2-(p-tolyl) acetic acid for2-(methylthio) acetic acid. 1H NMR (500 MHz, DMSO-d₆) δ 12.12 (s, 1H),7.66 (dd, J=8.8, 2.3 Hz, 1H), 7.51 (d, J=2.3 Hz, 1H), 7.27 (dd, J=13.4,10.6 Hz, 2H), 7.07 (s, 4H), 6.93 (d, J=9.0 Hz, 1H), 5.97 (t, J=2.3 Hz,1H), 5.00 (d, J=7.9 Hz, 1H), 4.25 (d, J=12.9 Hz, 1H), 3.85 (d, J=13.7Hz, 1H), 3.72-3.60 (m, 3H), 3.55 (s, 3H), 3.14-3.02 (m, 4H), 2.71 (t,J=11.4 Hz, 1H), 2.26 (d, J=13.3 Hz, 3H), 1.80 (dd, J=35.6, 11.4 Hz, 2H),1.11 (ddd, J=25.7, 17.1, 7.2 Hz, 2H). MS (ESI+) m/z 533.2 (M+H)+.

Example 1014-[2-{[1-(benzylsulfonyl)piperidin-4-yl]amino}-5-(methylsulfonyl)phenyl]-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one

A 4 mL vial was charged with Example 84c (23 mg, 0.06 mmol) in 1.5 mL ofdichloromethane, followed by the addition of phenyl methane sulfonylchloride (13 mg, 0.07 mmol), and diisopropyl ethyl amine (30 μL, 0.18mmol). The reaction mixture was allowed to stir at ambient temperatureovernight. The reaction mixture was concentrated and the residue waspurified by reverse phase HPLC (C18, CH₃CN/water (0.1% TFA), 0-100%gradient) to afford the TFA salt of the title compound. ¹H NMR (400 MHz,DMSO-d₆/D₂O) δ 7.69 (dd, J=8.7, 2.4 Hz, 1H), 7.54 (d, J=2.3 Hz, 1H),7.41-7.28 (m, 5H), 7.18 (s, 1H), 6.93 (d, J=8.7 Hz, 1H), 6.01 (d, J=2.8Hz, 1H), 4.29 (s, 2H), 3.58 (s, 3H), 3.47-3.36 (m, 2H), 3.07 (s, 3H),2.95-2.85 (m, 2H), 1.92-1.83 (m, 2H), 1.34-1.20 (m, 2H). MS (ESI+) m/z555.1 (M+H)⁺.

Example 1026-methyl-4-{5-(methylsulfonyl)-2-[(1-{[(E)-2-phenylethenyl]sulfonyl}piperidin-4-yl)amino]phenyl}-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one

The TFA salt of Example 102 was prepared according to the procedure usedfor the preparation of Example 101, substituting(E)-2-phenylethenesulfonyl chloride for phenyl methane sulfonylchloride. ¹H NMR (400 MHz, DMSO-d₆/D₂O) δ 7.71-7.59 (m, 3H), 7.53 (d,J=2.3 Hz, 1H), 7.48-7.43 (m, 3H), 7.41-7.33 (m, 1H), 7.25 (d, J=2.8 Hz,1H), 7.17 (s, 1H), 7.11-7.02 (m, 1H), 6.93 (d, J=8.7 Hz, 1H), 6.00 (d,J=2.8 Hz, 1H), 3.65-3.55 (m, 2H), 3.55 (s, 4H), 3.51 (d, J=3.4 Hz, 1H),3.06 (s, 3H), 2.97-2.86 (m, 2H), 2.03-1.91 (m, 2H), 1.47-1.34 (m, 2H).MS (ESI+) m/z 567.1 (M+H)⁺.

Example 103N-{4-[(4-{[2-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-4-(methylsulfonyl)phenyl]amino}piperidin-1-yl)sulfonyl]phenyl}acetamide

The TFA salt of Example 103 was prepared according to the procedure usedfor the preparation of Example 101, substituting4-acetamidobenzene-1-sulfonyl chloride for phenyl methane sulfonylchloride. ¹H NMR (400 MHz, DMSO-d₆/D₂O) δ 7.82-7.71 (m, 2H), 7.70-7.59(m, 3H), 7.56-7.46 (m, 1H), 7.30-7.20 (m, 1H), 7.14 (d, J=3.9 Hz, 1H),6.93-6.82 (m, 1H), 6.01-5.92 (m, 1H), 3.59-3.40 (m, 6H), 3.05 (s, 3H),2.67-2.54 (m, 2H), 2.12 (s, 3H), 1.98-1.86 (m, 2H), 1.46-1.28 (m, 2H),1.12-1.02 (m, 1H). MS (ESI+) m/z 598 (M+H)⁺.

Example 1044-[2-({1-[(4-methoxyphenyl)sulfonyl]piperidin-4-yl}amino)-5-(methylsulfonyl)phenyl]-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one

Example 104 was prepared according to the procedure used for thepreparation of Example 101, substituting 4-methoxybenzene-1-sulfonylchloride for phenyl methane sulfonyl chloride to provide the TFA salt ofthe title compound. ¹H NMR (400 MHz, DMSO-d₆/D₂O) δ 7.71-7.59 (m, 3H),7.56-7.47 (m, 1H), 7.30-7.21 (m, 1H), 7.18-7.07 (m, 3H), 6.93-6.82 (m,1H), 6.02-5.92 (m, 1H), 3.87 (s, 3H), 3.55 (s, 3H), 3.51-3.37 (m, 3H),3.05 (s, 3H), 2.65-2.54 (m, 2H), 2.01-1.86 (m, 2H), 1.46-1.28 (m, 2H).MS (ESI+) m/z 571.1 (M+H)⁺.

Example 1053-[(4-{[2-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-4-(methylsulfonyl)phenyl]amino}piperidin-1-yl)sulfonyl]benzonitrile

The TFA salt of Example 105 was prepared according to the procedure usedfor the preparation of Example 101, substituting3-cyanobenzene-1-sulfonyl chloride for phenyl methane sulfonyl chloride.¹H NMR (400 MHz, DMSO-d₆/D₂O) δ 8.16-8.05 (m, 2H), 8.05-7.96 (m, 1H),7.90-7.77 (m, 1H), 7.71-7.60 (m, 1H), 7.51 (d, J=2.4 Hz, 1H), 7.25 (t,J=3.2 Hz, 1H), 7.14 (s, 1H), 6.93-6.83 (m, 1H), 5.96 (t, J=2.5 Hz, 1H),3.60-3.53 (m, 4H), 3.53-3.44 (m, 3H), 3.05 (s, 3H), 2.78-2.63 (m, 2H),1.99-1.87 (m, 2H), 1.46-1.19 (m, 2H). MS (ESI+) m/z 566.1 (M+H)⁺.

Example 1066-methyl-4-[5-(methylsulfonyl)-2-{[1-(thiophen-2-ylsulfonyl)piperidin-4-yl]amino}phenyl]-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one

The TFA salt of Example 106 was prepared according to the procedure usedfor the preparation of Example 101, substituting thiophene-2-sulfonylchloride for phenyl methane sulfonyl chloride. ¹H NMR (400 MHz,DMSO-d₆/D₂O) δ 7.95 (dd, J=6.8, 2.9 Hz, 1H), 7.72-7.61 (m, 1H),7.61-7.48 (m, 2H), 7.25 (dd, J=8.4, 3.8 Hz, 2H), 7.15 (s, 1H), 6.90 (d,J=8.8 Hz, 1H), 5.97 (d, J=2.8 Hz, 1H), 3.66-3.48 (m, 4H), 3.46-3.33 (m,2H), 3.06 (s, 3H), 2.73 (ddd, J=12.6, 7.0, 3.9 Hz, 2H), 1.94 (ddd,J=9.4, 5.2, 2.3 Hz, 2H), 1.52-1.34 (m, 2H) MS (ESI+) m/z 546.9 (M+H)⁺.

Example 1076-methyl-4-[5-(methylsulfonyl)-2-({trans-4-[(thiophen-2-ylmethyl)amino]cyclohexyl}amino)phenyl]-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-oneExample 107a tert-butyl(trans-4-((2-bromo-4-(methylsulfonyl)phenyl)amino)cyclohexyl)carbamate

A solution of Example 21b (0.403 g, 1.592 mmol),N,N-diisopropylethylamine (0.320 mL, 1.831 mmol), and tert-butyl(trans-4-aminocyclohexyl)carbamate (0.352 g, 1.592 mmol) indimethylsulfoxide (12 mL) was stirred at 100° C. for 4 hours. To thecooled mixture was added dilute ammonium chloride solution and themixture was extracted twice with diethylether. The combined organiclayers were dried with anhydrous magnesium sulfate, filtered, andconcentrated. The residue was purified by chromatography (silica gel,25% ethyl acetate in heptane) to afford 0.39 g (55%) of the titlecompound.

Example 107b tert-butyl(trans-4-{[2-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-4-(methylsulfonyl)phenyl]amino}cyclohexyl)carbamate

Example 107a (0.380 g, 0.849 mmol), Example 1f (0.382 g, 0.892 mmol),tetrakis(triphenylphosphine)palladium (0) (0.098 g, 0.085 mmol), andcesium fluoride (0.387 g, 2.550 mmol) were combined and sparged withargon for 10 minutes. Dimethoxyethane (20 mL) and methanol (10 mL) wereadded and argon was bubbled through mixture for 15 min. The reactionmixture was stirred at 80° C. for 2 hours. To 25 mL of cooled reactionmixture was added 5N sodium hydroxide aqueous solution (2.0 mL) and themixture was stirred for 2 hours at room temperature. To the resultingmixture was added dilute ammonium chloride solution and extracted twicewith ethyl acetate. The combined organic layers were dried withanhydrous magnesium sulfate, filtered, and concentrated. The residue waspurified by chromatography (silica gel, 2% methanol in dichloromethane)to afford 0.24 g (63%) of the title compound.

Example 107c4-{2-[(trans-4-aminocyclohexyl)amino]-5-(methylsulfonyl)phenyl}-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one

A solution of Example 107b (0.025 g, 0.049 mmol) in dichloromethane (2.0mL) was stirred at room temperature. To this solution was added excesstrifluoroacetic acid (0.2 mL) and the mixture was stirred 2 hours atroom temperature. The mixture was neutralized slowly with sodiumcarbonate solution until pH was about 10, and then extracted twice withdichloromethane. The combined organic layers were dried with anhydrousmagnesium sulfate, filtered, and concentrated. The solid residue wastriturated with warm ethyl acetate, filtered, and dried to afford 0.020g (99%) of title compound.

Example 107d6-methyl-4-[5-(methylsulfonyl)-2-({trans-4-[(thiophen-2-ylmethyl)amino]cyclohexyl}amino)phenyl]-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one

A 4 mL vial was charged Example 107c (20 mg, 0.05 mmol), in 1.5 mL of1:1 dichloromethane: methanol to which was addedthiophene-2-carbaldehyde (6 mg, 0.08 mmol), and di-isopropyl ethyl amine(21 μL, 0.12 mmol). The reaction mixture was allowed to stir at ambienttemperature for 30 minutes after which was added Silica-cyanoborohydride(150 mg, loading 0.89 mmol/g), and the mixture was allowed to stirovernight. The reaction mixture was concentrated and the residue waspurified by reverse phase HPLC (C18, CH₃CN/water (0.1% TFA), 0-100%gradient) to afford the TFA salt of the title compound. ¹H NMR (400 MHz,DMSO-d₆/D₂O) δ 7.69 (dd, J=8.8, 2.3 Hz, 1H), 7.51 (d, J=2.3 Hz, 1H),7.34 (d, J=2.8 Hz, 1H), 7.26 (s, 1H), 6.90 (d, J=9.0 Hz, 1H), 6.02 (d,J=2.8 Hz, 1H), 3.57 (s, 3H), 3.43 (dd, J=32.4, 21.5 Hz, 1H), 3.10 (s,3H), 2.50 (d, J=6.9 Hz, 2H), 1.93 (d, J=10.4 Hz, 4H), 1.80-1.68 (m, 1H),1.31 (dd, J=23.1, 11.3 Hz, 2H), 1.08 (dt, J=13.9, 8.9 Hz, 2H), 0.89 (d,J=6.7 Hz, 6H). MS (ESI+) m/z 511.1 (M+H)⁺.

Example 108N-(4-{[(trans-4-{[2-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-4-(methylsulfonyl)phenyl]amino}cyclohexyl)amino]methyl}phenyl)acetamide

The TFA salt of Example 108 was prepared according to the procedure usedfor the preparation Example 107d substituting N-(4-formylphenyl)acetamide for thiophene-2-carbaldehyde. ¹H NMR (400 MHz, DMSO-d₆/D₂O) δ7.76 (ddd, J=21.3, 11.1, 5.5 Hz, 1H), 7.50 (dd, J=5.4, 3.0 Hz, 3H),7.38-7.14 (m, 4H), 6.90 (d, J=9.0 Hz, 1H), 6.01 (d, J=2.8 Hz, 1H), 3.57(s, 3H), 3.42 (dd, J=25.7, 14.7 Hz, 1H), 3.10 (s, 3H), 2.48-2.36 (m,1H), 2.04 (s, 3H), 1.92 (d, J=10.6 Hz, 4H), 1.27 (dd, J=23.5, 11.1 Hz,2H), 1.06 (dd, J=23.1, 11.5 Hz, 2H). MS (ESI+) m/z 562.1 (M+H)⁺.

Example 1094-[2-({trans-4-[(2,4-difluorobenzyl)amino]cyclohexyl}amino)-5-(methylsulfonyl)phenyl]-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one

The TFA salt of Example 109 was prepared according to the procedure usedfor the preparation of Example 107d, substituting2,4-difluorobenzaldehyde for thiophene-2-carbaldehyde. ¹H NMR (400 MHz,DMSO-d₆/D₂O) δ 7.68 (dd, J=8.7, 2.4 Hz, 1H), 7.53-7.44 (m, 2H), 7.33 (d,J=2.8 Hz, 1H), 7.25 (s, 1H), 7.12 (td, J=9.8, 2.6 Hz, 1H), 7.03 (td,J=8.6, 2.7 Hz, 1H), 6.89 (d, J=8.8 Hz, 1H), 6.01 (d, J=2.8 Hz, 1H), 3.57(s, 3H), 3.45-3.34 (m, 1H), 3.10 (s, 3H), 2.35-2.25 (m, 1H), 1.94-1.83(m, 6H), 1.29-1.12 (m, 2H), 1.14-0.98 (m, 2H). MS (ESI+) m/z 541.1(M+H)⁺.

Example 1106-methyl-4-[5-(methylsulfonyl)-2-({trans-4-[(naphthalen-2-ylmethyl)amino]cyclohexyl}amino)phenyl]-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one

The TFA salt of Example 110 was prepared according to the procedure usedfor the preparation of Example 107d, substituting 2-naphthaldehyde forthiophene-2-carbaldehyde. ¹H NMR (400 MHz, DMSO-d₆/D₂O) δ 7.87 (dd,J=17.8, 9.4 Hz, 4H), 7.68 (dd, J=8.8, 2.3 Hz, 1H), 7.58-7.42 (m, 4H),7.32 (d, J=2.8 Hz, 1H), 7.24 (s, 1H), 6.90 (d, J=9.0 Hz, 1H), 6.00 (d,J=2.8 Hz, 1H), 3.93 (s, 2H), 3.56 (s, 3H), 3.41 (t, J=11.1 Hz, 1H), 3.10(s, 3H), 2.42 (d, J=10.8 Hz, 1H), 1.93 (t, J=12.8 Hz, 4H), 1.28 (dd,J=23.5, 11.0 Hz, 2H), 1.06 (dd, J=22.6, 11.0 Hz, 2H). MS (ESI+) m/z555.1 (M+H)⁺.

Example 1114-[2-({trans-4-[(2-methoxyethyl)amino]cyclohexyl}amino)-5-(methylsulfonyl)phenyl]-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one

The TFA salt of Example 111 was prepared according to the procedure usedfor the preparation of Example 107d, substituting 2-methoxyacetaldehydefor thiophene-2-carbaldehyde. ¹H NMR (400 MHz, DMSO-d₆/D₂O) δ 7.69 (dd,J=8.8, 2.3 Hz, 1H), 7.51 (d, J=2.3 Hz, 1H), 7.34 (d, J=2.8 Hz, 1H), 7.26(s, 1H), 6.90 (d, J=9.0 Hz, 1H), 6.02 (d, J=2.8 Hz, 1H), 3.57 (s, 3H),3.41 (dt, J=16.0, 8.0 Hz, 3H), 3.33-3.19 (m, 4H), 3.10 (s, 3H), 2.77 (t,J=5.5 Hz, 2H), 1.90 (t, J=12.4 Hz, 4H), 1.29-1.14 (m, 2H), 1.15-1.02 (m,2H). MS (ESI+) m/z 473.2 (M+H)⁺.

Example 1126-methyl-4-{2-[(trans-4-{[3-(methylsulfanyl)propyl]amino}cyclohexyl)amino]-5-(methylsulfonyl)phenyl}-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one

The TFA salt of Example 112 as prepared according to the procedure usedfor the preparation of Example 107d, substituting 3-(methylthio)propanalfor thiophene-2-carbaldehyde. ¹H NMR (400 MHz, DMSO-d₆/D₂O) δ 7.72-7.64(m, 1H), 7.58-7.47 (m, 1H), 7.38-7.29 (m, 1H), 7.29-7.21 (m, 1H),6.94-6.86 (m, 1H), 6.02 (d, J=2.8 Hz, 1H), 3.57 (s, 3H), 3.50-3.30 (m,1H), 3.10 (s, 3H), 2.73-2.60 (m, 2H), 2.50 (d, J=7.2 Hz, 2H), 2.03 (s,3H), 1.98-1.83 (m, 4H), 1.74-1.61 (m, 2H), 1.34-1.15 (m, 2H), 1.15-0.97(m, 2H) MS (ESI+) m/z 503.1 (M+H)⁺.

Example 1134-[2-({trans-4-[(4-chlorobenzyl)amino]cyclohexyl}amino)-5-(methylsulfonyl)phenyl]-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one

The TFA salt of Example 113 was prepared according to the procedure usedfor the preparation of Example 107d, substituting 4-chlorobenzaldehydefor thiophene-2-carbaldehyde. ¹H NMR (400 MHz, DMSO-d₆/D₂O) δ 7.68 (dd,J=8.8, 2.3 Hz, 1H), 7.50 (d, J=2.3 Hz, 1H), 7.42-7.27 (m, 5H), 7.24 (s,1H), 6.89 (d, J=9.0 Hz, 1H), 6.01 (d, J=2.8 Hz, 1H), 3.56 (s, 3H), 3.39(t, J=10.9 Hz, 1H), 3.10 (s, 3H), 2.33 (d, J=10.3 Hz, 1H), 1.89 (s, 6H),1.22 (dd, J=23.8, 10.7 Hz, 2H), 1.05 (dd, J=23.2, 10.9 Hz, 2H). MS(ESI+) m/z 539.1 (M+H)⁺.

Example 1144-[2-(2,4-difluorophenoxy)-5-(methylsulfonyl)phenyl]-6-methyl-2-{[4-(1,3-thiazol-2-yl)piperazin-1-yl]methyl}-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-oneExample 114a ethyl4-bromo-7-methoxy-1-tosyl-1H-pyrrolo[2,3-c]pyridine-2-carboxylate

To a solution of Example 1c (10.5 g, 27.5 mmol) in tetrahydrofuran (170mL) was added dropwise lithium diisopropylamide (20.7 mL, 41.4 mmol) at-70° C. and then stirred between −70° C. and −50° C. for 45 min. Afterthat, to the stirred resulting mixture at −70° C. was added ethylcarbonochloridate (4.48 g, 41.3 mmol) dropwise. The mixture was stirredat −70° C. for 1.5 hours. After the reaction was complete, the reactionmixture was quenched with 20% aqueous ammonium chloride, extracted withethyl acetate (150 mL). The combined organic layer was dried overanhydrous Na₂SO₄, concentrated in vacuum to give the crude product,which was washed with dichloromethane to give the title compound (10 g,80%) as a white solid.

Example 114b ethyl4-bromo-7-oxo-1-tosyl-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-2-carboxylate

To a mixture of Example 114a (32.5 g, 71.7 mmol) and sodium iodide(16.12 g, 108 mmol) in acetonitrile (554 mL) was addedchlorotrimethylsilane (11.68 g, 108 mmol) dropwise at ambienttemperature. The resulting mixture was stirred at ambient temperaturefor 1 hour. Then water (0.685 g, 38.0 mmol) was added dropwise to thereaction mixture and stirred at 65° C. for 3 hours. The reaction mixturewas cooled to ambient temperature and filtered. The precipitate wasdissolved in dichloromethane. The mixture was filtered again and thecombined filtrate was concentrated under reduced pressure to give abrown solid which was washed with petroleum and dichloromethane toafford the title compound (23 g, 52.4 mmol, 73.0% yield) as light yellowsolid.

Example 114c ethyl4-bromo-6-methyl-7-oxo-1-tosyl-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-2-carboxylate

To a solution of Example 114b (7.5 g, 17.07 mmol) in tetrahydrofuran(100 mL) was added sodium hydride (0.520 g, 21.68 mmol) in portions at0° C. and stirred for 30 minutes. Iodomethane (3.64 g, 25.6 mmol) wasadded dropwise to the above mixture at 0° C. The resulting mixture wasstirred at ambient temperature for 3 hours and another portion ofiodomethane (3.64 g, 25.6 mmol) was added at 0° C. The reaction mixturewas stirred at ambient temperature for 12 hours. The reaction mixturewas quenched with 20% aqueous ammonium chloride and extracted with ethylacetate three times. The combined organic extracts were dried overanhydrous Na₂SO₄ and concentrated in vacuo. The resulting crude productwas purified by column chromatography on silica gel (hexane/ethylacetate gradient) to provide a yellow crude product which was washedwith methanol to give the title compound (15.3 g, 80% yield) as whitesolid.

Example 114d ethyl6-methyl-7-oxo-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-tosyl-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-2-carboxylate

Example 114d was prepared according to the procedure used for thepreparation of Example if, substituting Example 114c for Example 1e.

Example 114e ethyl4-(2-fluoro-5-(methylsulfonyl)phenyl)-6-methyl-7-oxo-1-tosyl-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-2-carboxylate

Example 114e was prepared according to the procedure used for thepreparation of Example 16j, substituting Example 114d for Example 16f,and Example 21b for Example 16i, respectively.

Example 114f ethyl4-(2-(2,4-difluorophenoxy)-5-(methylsulfonyl)phenyl)-6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-2-carboxylate

A mixture of Example 114e (0.405 g, 1.032 mmol), 2,4-difluorophenol(0.161 g, 1.239 mmol), and cesium carbonate (0.404 g, 1.239 mmol) inDMSO (5 mL) was heated at 110° C. overnight. The reaction mixture waspartitioned between water and ethyl acetate. The aqueous layer wasextracted with additional ethyl acetate three times. The combinedorganic layers were washed with brine, dried over anhydrous MgSO₄,filtered, and concentrated. The residue was purified by flashchromatography on silica gel eluting with 1:100 methanol/ethyl acetateto give the title compound (0.44 g, 0.876 mmol, 85% yield).

Example 114g4-[2-(2,4-difluorophenoxy)-5-(methylsulfonyl)phenyl]-2-(hydroxymethyl)-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one

To a suspension of Example 114f (0.20 g, 0.40 mmol) in tetrahydrofuran(5 mL) stirring at 0° C. was added lithium aluminum hydride (1M intetrahydrofuran, 0.398 mL, 0.398 mmol) and the mixture was stirred at 0°C. for two hours. The solvent was evaporated under reduced pressure andthe residue was partitioned between ethyl acetate (30 mL) and water (20mL). The mixture was filtered to remove the undissolved materials. Theaqueous layer was extracted with ethyl acetate (2×30 mL). The combinedorganic layers were dried over anhydrous sodium sulfate, filtered, andconcentrated. The residue was triturated with dichloromethane and theresulting solid was filtered and dried to provide the title compound(0.10 g, 55% yield).

Example 114h4-(2-(2,4-difluorophenoxy)-5-(methylsulfonyl)phenyl)-6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-2-carbaldehyde

To the solution of Example 114i (1.0 g, 2.2 mmol) in dichloromethane (50mL) at 0° C. was added Dess-Martin Periodinane (1.84 g, 4.34 mmol) andthe reaction mixture was stirred at 0° C. for 30 minutes. The reactionmixture was then stirred at ambient temperature for three hours. Asolution of sodium bisulfite (0.9 g, 9 mmol) in saturated aqueous sodiumbicarbonate (5 mL) was added, and the reaction mixture was stirred for15 minutes and extracted with ethyl acetate. The organic layer was dried(anhydrous sodium sulfate), filtered, and concentrated to provide thetitle compound (0.80 g, 70% yield).

Example 114i4-[2-(2,4-difluorophenoxy)-5-(methylsulfonyl)phenyl]-6-methyl-2-{[4-(1,3-thiazol-2-yl)piperazin-1-yl]methyl}-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one

Example 114i was prepared according to the procedure used for thepreparation of Example 16o, substituting 2-(piperazin-1-yl)thiazole for1-(pyridin-4-yl)piperazine, and Example 114h for Example 16n,respectively. ¹H NMR (400 MHz, DMSO-d₆) δ 12.02 (s, 1H), 7.99 (d, J=2.4Hz, 1H), 7.87 (dd, J=8.7, 2.4 Hz, 1H), 7.54-7.50 (m, 1H), 7.47-7.38 (m,2H), 7.21-7.08 (m, 2H), 6.99 (d, J=8.2 Hz, 1H), 6.81 (d, J=3.6 Hz, 1H),6.19 (s, 1H), 3.65 (s, 2H), 3.58 (s, 3H), 3.33-3.28 (m, 4H), 3.26 (s,3H), 2.48-2.40 (m, 4H). MS (ESI+) m/z 612.2 (M+H)⁺.

Example 1152-[(4-cyclopropylpiperazin-1-yl)methyl]-4-[2-(2,4-difluorophenoxy)-5-(methylsulfonyl)phenyl]-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one

Example 115 was prepared according to the procedure used for thepreparation of Example 16o, substituting 1-cyclopropylpiperazine for1-(pyridin-4-yl)piperazine, and Example 114h for Example 16n,respectively. ¹H NMR (400 MHz, DMSO-d₆) δ 11.95 (s, 1H), 7.98 (d, J=2.4Hz, 1H), 7.87 (dd, J=8.7, 2.4 Hz, 1H), 7.56-7.50 (m, 1H), 7.46-7.37 (m,2H), 7.16 (dd, J=11.8, 5.5 Hz, 1H), 7.00 (d, J=8.6 Hz, 1H), 6.12 (s,1H), 3.58 (s, 3H), 3.54 (s, 2H), 3.26 (s, 3H), 2.46-2.13 (m, 8H),1.55-1.48 (m, 1H), 0.38-0.30 (m, 2H), 0.19-0.16 (m, 2H). MS (ESI+) m/z569.2 (M+H)⁺.

Example 1164-[2-(2,4-difluorophenoxy)-5-(methylsulfonyl)phenyl]-6-methyl-2-{[4-(tetrahydro-2H-pyran-4-yl)piperazin-1-yl]methyl}-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one

Example 116 was prepared according to the procedure used for thepreparation of Example 16o, substituting1-(tetrahydro-2H-pyran-4-yl)piperazine for 1-(pyridin-4-yl)piperazine,and Example 114h for Example 16n, respectively. ¹H NMR (400 MHz, CD3OD)δ 8.07 (d, J=2.3 Hz, 1H), 7.94 (dd, J=8.7, 2.4 Hz, 1H), 7.38 (s, 1H),7.27-7.15 (m, 2H), 7.07-6.96 (m, 2H), 6.30 (s, 1H), 4.03-3.94 (m, 2H),3.75-3.66 (m, 5H), 3.39 (t, J=11.3 Hz, 2H), 3.21 (s, 3H), 2.76-2.33 (m,9H), 1.82 (d, J=10.9 Hz, 2H), 1.56-1.40 (m, 2H). MS (ESI+) m/z 613.2(M+H)⁺.

Example 1174-[2-(2,4-difluorophenoxy)-5-(ethylsulfonyl)phenyl]-6-methyl-2-(1-phenyl-1H-pyrazol-5-yl)-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-oneExample 117a4-bromo-6-methyl-2-(1-phenyl-1H-pyrazol-5-yl)-1-tosyl-1H-pyrrolo[2,3-c]pyridin-7(6H)-one

Example 117a was prepared according to the procedure used for thepreparation of Example 16j, substituting(1-phenyl-1H-pyrazol-5-yl)boronic acid for Example 16f, and Example 63cfor Example 16i, respectively.

Example 117b4-(5-(ethylsulfonyl)-2-fluorophenyl)-6-methyl-2-(1-phenyl-1H-pyrazol-5-yl)-1-tosyl-1H-pyrrolo[2,3-c]pyridin-7(6H)-one

Example 117b was prepared according to the procedure used for thepreparation of Example 16j, substituting Example 63e for Example 16f,and Example 117a for Example 16i, respectively.

Example 117c4-[2-(2,4-difluorophenoxy)-5-(ethylsulfonyl)phenyl]-6-methyl-2-(1-phenyl-1H-pyrazol-5-yl)-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one

Example 117c was prepared according to the procedure used for thepreparation of Example 114f, substituting Example 117b for Example 114e.¹H NMR (400 MHz, CD3OD) δ 7.88 (d, J=2.3 Hz, 1H), 7.84 (dd, J=8.6, 2.4Hz, 1H), 7.78 (d, J=2.0 Hz, 1H), 7.44-7.33 (m, 6H), 7.18-7.11 (m, 1H),7.10-7.03 (m, 1H), 7.02-6.95 (m, 2H), 6.87 (d, J=2.0 Hz, 1H), 5.92 (s,1H), 3.69 (s, 3H), 3.23 (q, J=7.4 Hz, 2H), 1.25 (t, J=7.4 Hz, 3H). MS(ESI+) m/z 587.0 (M+H)⁺.

Example 1184-[2-(2,4-difluorophenoxy)-5-(ethylsulfonyl)phenyl]-6-methyl-2-[2-(morpholin-4-yl)pyridin-3-yl]-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-oneExample 118a4-bromo-2-(2-fluoropyridin-3-yl)-6-methyl-1-tosyl-1H-pyrrolo[2,3-c]pyridin-7(6H)-one

Example 118a was prepared according to the procedure used for thepreparation of Example 16j, substituting (2-fluoropyridin-3-yl)boronicacid for Example 16f, and Example 63c for Example 16i, respectively.

Example 118b4-bromo-6-methyl-2-(2-morpholinopyridin-3-yl)-1H-pyrrolo[2,3-c]pyridin-7(6H)-one

Cesium carbonate (0.103 g, 0.315 mmol), morpholine (0.091 g, 1.050mmol), and Example 118a (0.05 g, 0.105 mmol) were combined in DMSO (1mL) and heated at 120° C. for 18 hours in sealed tube. The mixture waspartitioned between ethyl acetate and water. The combined organics werewashed with brine, dried (anhydrous MgSO₄), filtered, and concentratedto a tan oil that was purified by Prep HPLC (C18, 0-100%acetonitrile/water (0.1% TFA) gradient) to give the title compound(0.027 g, 0.070 mmol, 67% yield).

Example 118c4-(5-(ethylsulfonyl)-2-fluorophenyl)-6-methyl-2-(2-morpholinopyridin-3-yl)-1H-pyrrolo[2,3-c]pyridin-7(6H)-one

Example 118c was prepared according to the procedure used for thepreparation of Example 16j, substituting Example 63e for Example 16f,and Example 118b for Example 16i, respectively.

Example 118d4-[2-(2,4-difluorophenoxy)-5-(ethylsulfonyl)phenyl]-6-methyl-2-[2-(morpholin-4-yl)pyridin-3-yl]-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one

Example 118d was prepared according to the procedure used for thepreparation of Example 114f, substituting Example 118c for Example 114e.¹H NMR (400 MHz, CD3OD) δ 8.25 (dd, J=4.9, 1.8 Hz, 1H), 8.07 (d, J=2.3Hz, 1H), 7.92 (dd, J=8.7, 2.4 Hz, 1H), 7.86 (dd, J=7.6, 1.8 Hz, 1H),7.43 (s, 1H), 7.27-7.14 (m, 2H), 7.12-7.06 (m, 2H), 7.00 (m, 1H), 6.69(s, 1H), 3.78-3.74 (m, 4H), 3.74 (s, 3H), 3.28 (q, J=7.4 Hz, 2H),3.10-3.05 (m, 4H), 1.29 (t, J=7.4 Hz, 3H). MS (ESI+) m/z 606.1 (M+H)⁺

Example 1194-[2-{2-[(cyclopropylmethyl)amino]-6-methylphenoxy}-5-(ethylsulfonyl)phenyl]-N-ethyl-6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-2-carboxamideExample 119a ethyl4-(5-(ethylsulfonyl)-2-fluorophenyl)-6-methyl-7-oxo-1-tosyl-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-2-carboxylate

Example 119a was prepared according to the procedure used for thepreparation of Example 16j, substituting Example 114d for Example 16f.

Example 119b4-(5-(ethylsulfonyl)-2-fluorophenyl)-6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-2-carboxylicacid

A mixture of Example 119a (2.05 g, 3.66 mmol), and 2.0 N sodiumhydroxide (7.31 mL, 14.63 mmol) in dioxane (15 mL) was heated at 90° C.for 2 hours. The reaction mixture was partially concentrated, thenquenched with 0.1 N HCl. The resulting solid was collected by filtrationand dried to give the title compound (1.32 g, 3.49 mmol, 95% yield).

Example 119cN-ethyl-4-(5-(ethylsulfonyl)-2-fluorophenyl)-6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-2-carboxamide

A mixture of Example 119b (0.74 g, 1.956 mmol), oxalyl chloride (0.514mL, 5.87 mmol), and dimethylformamide (0.151 mL, 1.956 mmol) indichloromethane (30 mL) was stirred for 2 hours. The solvent wasremoved, and the residue was treated with tetrahydrofuran (10 mL) anddimethylformamide (5 mL). To this solution was added 1.0 N ethanamine intetrahydrofuran (15.65 mL, 15.65 mmol). The reaction mixture was stirredat ambient temperature for 3 hours, tetrahydrofuran was removed underreduced pressure, and the residue was partitioned between water andethyl acetate. The aqueous layer was extracted with additional ethylacetate three times. The combined organic layers were washed with brine,dried over anhydrous MgSO₄, filtered, and concentrated. The residue waspurified by flash column chromatography on silica gel eluting with 5%methanol in ethyl acetate to give the title compound (0.7 g, 1.727 mmol,88% yield).

Example 119d4-(2-(2-amino-6-methylphenoxy)-5-(ethylsulfonyl)phenyl)-N-ethyl-6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-2-carboxamide

A mixture of Example 119c (0.081 g, 0.2 mmol), 2-amino-6-methylphenol(0.049 g, 0.400 mmol), and cesium carbonate (0.130 g, 0.400 mmol) inDMSO (2 mL) was heated at 110° C. for 16 hours. The reaction mixture wasdiluted with ethyl acetate. The solid was removed by filtration. Thefiltrate was concentrated. The residue was purified by Prep HPLC (C18,0-100% acetonitrile/water (0.1% TFA) gradient) to give the titlecompound as trifluroacetic acid salt. (0.055 g, 0.088 mmol, 44.2%yield).

Example 119e4-[2-{2-[(cyclopropylmethyl)amino]-6-methylphenoxy}-5-(ethylsulfonyl)phenyl]-N-ethyl-6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-2-carboxamide

A mixture of Example 119d (0.02 g, 0.032 mmol), cyclopropanecarbaldehyde(2.93 mg, 0.042 mmol) and sodium cyanotrihydroborate (2.62 mg, 0.042mmol) in 1,2-dichloroethane (1 mL) was stirred at ambient temperaturefor 16 hours. Solvent was removed under reduced pressure, and theresidue was purified by Prep HPLC (C18, 0-100% acetonitrile/water (0.1%TFA) gradient) to afford the title compound as the trifluoroacetic acidsalt (0.019 g, 0.028 mmol, 87% yield). ¹H NMR (400 MHz, DMSO-d₆) δ 12.35(d, J=2.4 Hz, 1H), 8.35 (t, J=5.3 Hz, 1H), 7.91 (d, J=2.4 Hz, 1H), 7.82(dd, J=8.8, 2.4 Hz, 1H), 7.60 (s, 1H), 7.00 (t, J=7.8 Hz, 1H), 6.85 (d,J=2.1 Hz, 1H), 6.70 (dd, J=27.9, 8.3 Hz, 2H), 6.51 (d, J=7.5 Hz, 1H),3.61 (s, 3H), 3.36-3.21 (m, 4H), 2.92 (s, 2H), 1.89 (s, 3H), 1.18-1.07(m, 6H), 0.95 (tt, J=9.7, 3.5 Hz, 1H), 0.32 (dt, J=8.2, 3.0 Hz, 2H),0.06 (d, J=3.7 Hz, 1H). MS (ESI+) m/z 613.2 (M+H)⁺.

Example 1204-[2-(2-chloro-6-methylphenoxy)-5-(ethylsulfonyl)phenyl]-N-(cyanomethyl)-6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-2-carboxamideExample 120a2-(2-bromo-4-(ethylsulfonyl)phenoxy)-1-chloro-3-methylbenzene

Example 120a was prepared according to the procedure used for thepreparation of Example 114f, substituting Example 16i for Example 114e,and 2-chloro-6-methylphenol for 2,4-difluorophenol, respectively.

Example 120b ethyl4-(2-(2-chloro-6-methylphenoxy)-5-(ethylsulfonyl)phenyl)-6-methyl-7-oxo-1-tosyl-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-2-carboxylate

Example 120b was prepared according to the procedure used for thepreparation of Example 16j, substituting Example 120a for Example 16i,and substituting Example 114d for Example 16f.

Example 120c4-(2-(2-chloro-6-methylphenoxy)-5-(ethylsulfonyl)phenyl)-6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-2-carboxylicacid

Example 120c was prepared according to the procedure used for thepreparation of Example 119b, substituting Example 120b for Example 119a.

Example 120d4-[2-(2-chloro-6-methylphenoxy)-5-(ethylsulfonyl)phenyl]-N-(cyanomethyl)-6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-2-carboxamide

In a 4 mL vial a solution of Example 120c (15 mg, 0.03 mmol) indimethylacetamide (0.3 mL) was added, followed by a solution ofO-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate (14 mg, 0.04 mmol) in dimethylacetamide (0.3 mL).Then a solution of 2-aminoacetonitrile (0.04 mmol) in dimethylacetamide(0.09 mL) was added followed by diisopropylethylamine (16 μL, 0.06mmol). The reaction mixture was shaken at 100° C. for 10 minutes. Thereaction mixture was then purified by Prep HPLC (C18, 0-100%acetonitrile/water (0.1% TFA) gradient) to give the title product. ¹HNMR (DMSO-d₆) δ: 7.94 (d, J=2.4 Hz, 1H), 7.81 (dd, J=8.7, 2.4 Hz, 1H),7.50 (s, 1H), 7.47 (d, J=7.9 Hz, 1H), 7.36 (d, J=7.6 Hz, 1H), 7.27 (t,J=7.9 Hz, 1H), 6.80 (s, 1H), 6.66 (d, J=8.7 Hz, 1H), 6.58 (s, 2H), 3.60(s, 3H), 3.30-3.34 (m, 4H), 2.11 (s, 3H), 1.14 (t, J=7.3 Hz, 3H). MS(ESI+) m/z 540.1 (M+H)⁺.

Example 1214-[2-(2-chloro-6-methylphenoxy)-5-(ethylsulfonyl)phenyl]-6-methyl-N-[1-(methylamino)-1-oxopropan-2-yl]-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-2-carboxamide

Example 121 was prepared according to the procedure used for thepreparation of Example 120d, substituting 2-amino-N-methylpropanamidefor 2-aminoacetonitrile. ¹H NMR (DMSO-d₆) δ: 7.93 (d, J=2.4 Hz, 1H);7.80 (dd, J=8.7, 2.4 Hz, 1H), 7.43 (s, 1H), 7.41 (dd, J=8.1, 1.6 Hz,1H), 7.30-7.33 (m, 1H), 7.21-7.26 (m, 1H), 6.94 (s, 1H), 6.68 (d, J=8.7Hz, 1H), 4.44 (q, J=7.1 Hz, 1H), 3.63 (s, 3H), 3.24-3.29 (m, 2H), 2.62(s, 3H), 2.11 (s, 3H), 1.33 (d, J=7.1 Hz, 3H), 1.19 (t, J=7.3 Hz, 3H),MS (ESI+) m/z 585 (M+H)⁺.

Example 1224-[2-(2-chloro-6-methylphenoxy)-5-(ethylsulfonyl)phenyl]-6-methyl-7-oxo-N-[2-oxo-2-(piperidin-1-yl)ethyl]-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-2-carboxamide

Example 122 was prepared according to the procedure used for thepreparation of Example 120d, substituting2-amino-1-(piperidin-1-yl)ethanone for 2-aminoacetonitrile. ¹H NMR(DMSO-d₆) δ: 7.93 (d, J=2.3 Hz, 1H), 7.81 (dd, J=8.7, 2.4 Hz, 1H), 7.43(s, 1H), 7.38-7.42 (m, 1H), 7.29-7.34 (m, 1H), 7.20-7.26 (m, 1H), 6.92(s, 1H), 6.68 (d, J=8.7 Hz, 1H), 4.13 (s, 2H), 3.62 (s, 3H), 3.40-3.47(m, 4H), 3.24-3.28 (m, 2H), 2.11 (s, 3H), 1.46-1.65 (m, 6H), 1.18 (t,J=7.4 Hz, 3H). MS (ESI+) m/z 625 (M+H)⁺.

Example 1234-[2-(2-chloro-6-methylphenoxy)-5-(ethylsulfonyl)phenyl]-N-(2-cyanoethyl)-6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-2-carboxamide

Example 123 was prepared according to the procedure used for thepreparation of Example 120d, substituting 3-aminopropanenitrile for2-aminoacetonitrile. ¹H NMR (DMSO-d₆) δ: 7.93 (d, J=2.4 Hz, 1H), 7.81(dd, J=8.7, 2.4 Hz, 1H), 7.42 (s, 1H), 7.38-7.42 (m, 1H), 7.29-7.33 (m,1H), 7.23 (t, J=7.8 Hz, 1H), 6.92 (s, 1H), 6.69 (d, J=8.7 Hz, 1H), 3.62(s, 3H), 3.52 (t, J=6.5 Hz, 2H), 3.25-3.29 (m, 2H), 2.74 (t, J=6.5 Hz,2H), 2.11 (s, 3H), 1.19 (t, J=7.4 Hz, 3H). MS (ESI+) m/z 553 (M+H)⁺.

Example 1244-[2-(2-chloro-6-methylphenoxy)-5-(ethylsulfonyl)phenyl]-6-methyl-N-[2-(methylamino)-2-oxoethyl]-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-2-carboxamide

Example 124 was prepared according to the procedure used for thepreparation of Example 120d, substituting 2-amino-N-methylacetamide for2-aminoacetonitrile. ¹H NMR (DMSO-d₆) δ: 7.93 (d, J=2.4 Hz, 1H), 7.81(dd, J=8.7, 2.4 Hz, 1H), 7.43 (s, 1H), 7.39-7.42 (m, 1H), 7.29-7.33 (m,1H), 6.92 (s, 1H), 7.21-7.26 (m, 1H), 6.69 (d, J=8.7 Hz, 1H), 3.88 (s,2H), 3.62 (s, 3H), 3.25-3.29 (m, 2H), 2.64 (s, 3H), 2.11 (s, 3H), 1.19(t, J=7.5 Hz, 3H). MS (ESI+) m/z 571 (M+H)+.

Example 1254-[2-(2,4-difluorophenoxy)-5-(methylsulfonyl)phenyl]-6-methyl-2-{[4-(1-methylpiperidin-4-yl)piperazin-1-yl]methyl}-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one

In a 4 mL vial was added the Example 114h (10 mg, 0.02 mmol) in 1Msolution of ammonium acetate/acetic acid buffer in methanol (pH=4) (1.0mL) followed by the addition of 1-(1-methylpiperidin-4-yl)piperazine(0.02) mmol) in the buffer solution (0.06 mL). After that, 75 mg ofMP-Cyanoborohydride resin (0.89 mmol/g) was added and the resultingmixture was shaken at 60° C. overnight. The solid was filtered off, andthe filtrate was concentrated. The residue was purified by Prep HPLC(C18, 0-100% acetonitrile/water (0.1% TFA) gradient) to give the titlecompound. ¹H NMR (DMSO-d₆) δ: 7.99 (d, J=2.4 Hz, 1H), 7.93 (dd, J=8.7,2.4 Hz, 1H), 7.41 (s, 1H), 7.25-7.38 (m, 2H), 7.05-7.18 (m, 2H), 6.38(s, 1H), 4.19 (s, 2H), 3.61 (s, 3H), 3.39-3.56 (m, 2H), 3.24 (s, 3H),2.84-3.09 (m, 11H), 2.80 (s, 3H), 2.07 (s, 2H), 1.75 (s, 2H). MS (ESI+)m/z 626 (M+H)⁺.

Example 1264-[2-(2,4-difluorophenoxy)-5-(methylsulfonyl)phenyl]-6-methyl-2-{[4-(pyridin-2-yl)-1,4-diazepan-1-yl]methyl}-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one

Example 126 was prepared according to the procedure used for thepreparation of Example 125, substituting 1-(pyridin-2-yl)-1,4-diazepanefor 1-(1-methylpiperidin-4-yl)piperazine. ¹H NMR (DMSO-d₆) δ: 8.03-8.14(m, 1H), 7.98-8.03 (m, 1H), 7.94 (dd, J=8.6, 2.4 Hz, 1H), 7.61-7.74 (m,1H), 7.42 (s, 1H), 7.25-7.36 (m, 2H), 7.05-7.15 (m, 2H), 6.81 (d, J=8.7Hz, 1H), 6.74 (dd, J=7.2, 5.4 Hz, 1H), 6.50 (s, 1H), 4.48 (s, 2H), 3.96(s, 2H), 3.62 (d, J=6.5 Hz, 5H), 3.39 (d, J=5.1 Hz, 4H), 3.24 (s, 3H),2.11-2.24 (m, 2H). MS (ESI+) m/z 620 (M+H)+.

Example 1274-[2-(2,4-difluorophenoxy)-5-(methylsulfonyl)phenyl]-2-{[3-(furan-2-yl)morpholin-4-yl]methyl}-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one

Example 127 was prepared according to the procedure used for thepreparation of Example 125, substituting 3-(furan-2-yl)morpholine for1-(1-methylpiperidin-4-yl)piperazine, to provide the title compound. ¹HNMR (DMSO-d₆) δ: 7.96-8.05 (m, 1H), 7.86-7.96 (m, 1H), 7.59-7.70 (m,1H), 7.38 (s, 1H), 7.25-7.37 (m, 2H), 7.03-7.12 (m, 2H), 6.57-6.64 (m,1H), 6.46-6.53 (m, 1H), 6.23 (s, 1H), 4.04-4.12 (m, 1H), 3.66-4.01 (m,6H), 3.60 (s, 3H), 3.24 (s, 3H), 2.96-3.02 (m, 1H), 2.64-2.72 (m, 1H).MS (ESI+) m/z 596 (M+H)+.

Example 1284-[2-(2,4-difluorophenoxy)-5-(methylsulfonyl)phenyl]-2-{[4-(3,5-dimethyl-4H-1,2,4-triazol-4-yl)piperidin-1-yl]methyl}-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one

Example 128 was prepared according to the procedure used for thepreparation of Example 125, substituting4-(3,5-dimethyl-4H-1,2,4-triazol-4-yl)piperidine for1-(1-methylpiperidin-4-yl)piperazine. ¹H NMR (DMSO-d₆) δ: 7.98-8.04 (m,1H), 7.94 (dd, J=8.7, 2.4 Hz, 1H), 7.44 (s, 1H), 7.26-7.37 (m, 2H),7.06-7.14 (m, 2H), 6.53 (s, 1H), 4.50-4.57 (m, 1H), 4.48 (s, 2H), 3.63(s, 3H), 3.50-3.59 (m, 2H), 3.24 (s, 3H), 3.19 (t, J=12.3 Hz, 2H), 2.38(s, 3H), 2.22-2.31 (m, 2H), 2.20 (s, 3H), 2.06-2.16 (m, 2H). MS (ESI+)m/z 623 (M+H)+.

Example 1294-[2-(2,4-difluorophenoxy)-5-(methylsulfonyl)phenyl]-2-{[3-(3,5-dimethyl-1H-pyrazol-1-yl)azetidin-1-yl]methyl}-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one

Example 129 was prepared according to the procedure used for thepreparation of Example 125, substituting1-(azetidin-3-yl)-3,5-dimethyl-1H-pyrazole for1-(1-methylpiperidin-4-yl)piperazine. ¹H NMR (DMSO-d₆) δ: 7.98-8.01 (m,1H), 7.93 (dd, J=8.7, 2.4 Hz, 1H), 7.42 (s, 1H), 7.25-7.33 (m, 2H),7.02-7.11 (m, 2H), 6.50 (s, 1H), 5.88 (s, 1H), 5.12-5.27 (m, 1H), 4.65(s, 2H), 4.44-4.59 (m, 4H), 3.62 (s, 3H), 3.23 (s, 3H), 2.15 (d, J=8.9Hz, 6H). MS (ESI+) m/z 594 (M+H)+.

Example 1304-[2-(2,4-difluorophenoxy)-5-(methylsulfonyl)phenyl]-6-methyl-2-{[4-(morpholin-4-yl)piperidin-1-yl]methyl}-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one

Example 130 was prepared according to the procedure used for thepreparation of Example 125, substituting 4-(piperidin-4-yl)morpholinefor 1-(1-methylpiperidin-4-yl)piperazine. ¹H NMR (DMSO-d₆) δ: 8.00 (d,J=2.4 Hz, 1H), 7.94 (dd, J=8.7, 2.4 Hz, 1H), 7.43 (s, 1H), 7.25-7.38 (m,2H), 7.03-7.16 (m, 2H), 6.47 (s, 1H), 4.37 (s, 2H), 3.80-3.89 (m, 4H),3.62 (s, 3H), 3.50 (d, J=12.9 Hz, 2H), 3.27-3.32 (m, 1H), 3.24 (s, 3H),3.14-3.21 (m, 4H), 2.89-3.01 (m, 2H), 2.17-2.30 (m, 2H), 1.81-1.99 (m,2H). MS (ESI+) m/z 613 (M+H)+.

Example 1314-[2-(2,4-difluorophenoxy)-5-(methylsulfonyl)phenyl]-6-methyl-2-{[2-(3-methyl-1,2,4-oxadiazol-5-yl)pyrrolidin-1-yl]methyl}-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one

Example 131 was prepared according to the procedure used for thepreparation of Example 125, substituting3-methyl-5-(pyrrolidin-2-yl)-1,2,4-oxadiazole for1-(1-methylpiperidin-4-yl)piperazine. ¹H NMR (DMSO-d₆) δ: 7.94-8.02 (m,1H), 7.91 (dd, J=8.7, 2.4 Hz, 1H), 7.36 (s, 1H), 7.25-7.35 (m, 2H),7.02-7.13 (m, 2H), 6.20 (s, 1H), 4.35-4.44 (m, 1H), 4.02-4.24 (m, 2H),3.60 (s, 3H), 3.23 (s, 3H), 3.17-3.23 (m, 1H), 2.83-2.92 (m, 1H),2.29-2.41 (m, 1H), 2.27 (s, 3H), 2.03-2.13 (m, 1H), 1.85-2.02 (m, 2H).MS (ESI+) m/z 596 (M+H)+.

Example 1324-[2-(2,4-difluorophenoxy)-5-(methylsulfonyl)phenyl]-6-methyl-2-{[4-(pyridin-2-yl)piperazin-1-yl]methyl}-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one

Example 132 was prepared according to the procedure used for thepreparation of Example 125, substituting 1-(pyridin-2-yl)piperazine for1-(1-methylpiperidin-4-yl)piperazine. ¹H NMR (DMSO-d₆) δ: 8.10-8.18 (m,1H), 7.97-8.05 (m, 1H), 7.94 (dd, J=8.7, 2.4 Hz, 1H), 7.61-7.72 (m, 1H),7.43 (s, 1H), 7.24-7.37 (m, 2H), 7.04-7.13 (m, 2H), 6.92 (d, J=8.6 Hz,1H), 3.24 (s, 3H), 6.76-6.83 (m, 1H), 6.51 (s, 1H), 4.48 (s, 2H),3.65-3.88 (m, 4H), 3.62 (s, 3H), 3.24-3.29 (m, 4H). MS (ESI+) m/z 606(M+H)+.

Example 133N-ethyl-4-[5-(ethylsulfonyl)-2-{2-methyl-6-[(tetrahydrofuran-3-ylmethyl)amino]phenoxy}phenyl]-6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-2-carboxamide

Example 119d (30.5 mg, 0.060 mmol), 50% tetrahydrofuran-3-carbaldehydein water (0.015 mL, 0.078 mmol), and sodium cyanoborohydride (4.9 mg,0.078 mmol) were combined in 1,2-dichloroethane (1 mL). The reactionmixture was stirred at ambient temperature for 3 hours. To this reactionmixture was added 50% tetrahydrofuran-3-carbaldehyde in water (0.015 mL,0.078 mmol) and sodium cyanoborohydride (4.9 mg, 0.078 mmol). Thereaction mixture was stirred at ambient temperature for another 3 hours.To this reaction mixture was added 50% tetrahydrofuran-3-carbaldehyde inwater (0.015 mL, 0.078 mmol) and sodium cyanoborohydride (4.9 mg, 0.078mmol). The reaction mixture was stirred at ambient temperature foranother 16 hours, and partitioned with ethyl acetate and water. Theorganic layer was washed with saturated aqueous sodium chloride, driedwith anhydrous sodium sulfate, filtered, and concentrated. The residuewas purified by reverse phase HPLC (C18, 50-100% acetonitrile in 0.1%TFA/water) to provide the title compound (3.6 mg, 10%). ¹H NMR (400 MHz,DMSO-d₆) δ 12.35 (s, 1H), 8.33 (t, J=5.3 Hz, 1H), 7.91 (d, J=2.4 Hz,1H), 7.80 (dd, J=8.7, 2.4 Hz, 1H), 7.64 (s, 1H), 6.99 (dd, J=10.3, 5.4Hz, 1H), 6.86 (d, J=2.2 Hz, 1H), 6.71 (d, J=8.7 Hz, 1H), 6.65 (d, J=7.9Hz, 1H), 6.49 (d, J=7.3 Hz, 1H), 4.83 (s, br, 1H), 3.69-3.61 (m, 2H),3.59 (s, 3H), 3.58-3.51 (m, 2H), 3.32-3.25 (m, 4H), 3.08-2.99 (m, 2H),2.46-2.38 (m, 1H), 1.85 (s, 3H), 1.83-1.76 (m, 1H), 1.45-1.38 (m, 1H),1.17-1.10 (m, 6H). (ESI+) m/z 593 (M+H)⁺.

Example 134(2E)-3-{4-[2-(2,6-dimethylphenoxy)-5-(ethylsulfonyl)phenyl]-6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-2-yl}-N-ethylprop-2-enamideExample 134a (E)-ethyl3-(4-bromo-6-methyl-7-oxo-1-tosyl-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-2-yl)acrylate

A mixture of Example 63c (1.5 g, 2.96 mmol), PdCl₂(dppf)-CH₂Cl₂Adduct(0.242 g, 0.296 mmol),ethyl acrylate (0.592 g, 5.92 mmol), andtriethylamine (2.061 mL, 14.79 mmol) in dimethylformamide (15 mL) washeated at 100° C. for 1 hour. After cooling, the reaction mixture waspartitioned between water and ethyl acetate. The aqueous layer wasextracted with ethyl acetate two more times. The combined organic layerswere dried over anhydrous MgSO₄, filtered, and concentrated. The residuewas purified by flash chromatography on silica gel to afford the titlecompound (1 g, 1.460 mmol, 49.4% yield).

Example 134b (E)-ethyl3-(4-(5-(ethylsulfonyl)-2-fluorophenyl)-6-methyl-7-oxo-1-tosyl-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-2-yl)acrylate

Example 134b was prepared according to the procedure used for thepreparation of Example 16j, substituting Example 63e for Example 16f,and Example 134a for Example 16i, respectively.

Example 134c (E)-ethyl3-(4-(2-(2,6-dimethylphenoxy)-5-(ethylsulfonyl)phenyl)-6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-2-yl)acrylate

Example 134c was prepared according to the procedure used for thepreparation of Example 114f, substituting Example 134b for Example 114e,and 2,6-dimethylphenol for 2,4-difluorophenol, respectively.

Example 134d

Example 134d was prepared according to the procedure used for thepreparation of Example 119b, substituting Example 134c for Example 119a.

Example 134e(2E)-3-{4-[2-(2,6-dimethylphenoxy)-5-(ethylsulfonyl)phenyl]-6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-2-yl}-N-ethylprop-2-enamide

Example 134e was prepared according to the procedure used for thepreparation of Example 119c, substituting Example 134d for Example 119b.¹H NMR (400 MHz, CD₃OD) δ 8.03 (d, J=2.3 Hz, 1H), 7.81 (dd, J=8.7, 2.4Hz, 1H), 7.53 (d, J=15.8 Hz, 1H), 7.45 (s, 1H), 7.20-7.07 (m, 3H), 6.68(d, J=8.7 Hz, 1H), 6.66-6.57 (m, 2H), 3.75 (s, 3H), 3.37 (q, J=7.6 Hz,2H), 3.27 (q, J=7.4 Hz, 2H), 2.10 (s, 6H), 1.29 (t, J=7.4 Hz, 3H), 1.21(t, J=7.3 Hz, 3H). MS (ESI+) m/z 534.2 (M+H)⁺.

Example 1352-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)-4-[2-(2,6-dimethylphenoxy)-5-(methylsulfonyl)phenyl]-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-oneExample 135a 2-(2-bromo-4-(methylsulfonyl)phenoxy)-1,3-dimethylbenzene

To a mixture of Example 21b (3.027 g, 11.96 mmol), 2,6-dimethylphenol(1.534 g, 12.56 mmol) and cesium carbonate (4.68 g, 14.35 mmol) wasadded dimethyl sulfoxide (60 mL). The reaction mixture was heated at 80°C. for 1 hour, cooled to ambient temperature and acidified with 2 Naqueous hydrochloric acid. The solid was collected by filtration, washedwith water and then triturated with methanol. The filtrates werecombined and concentrated to remove methanol. A second crop precipitatedout of solution. The solid was collected by filtration, washed withwater and then triturated with methanol. The two portions were driedovernight in a vacuum oven at 70° C. to provide the title compound(3.486 g, 82%).

Example 135b ethyl4-(2-(2,6-dimethylphenoxy)-5-(methylsulfonyl)phenyl)-6-methyl-7-oxo-1-tosyl-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-2-carboxylate

Example 114d (4 g, 8 mmol), Example 135a (3.41 g, 9.6 mmol),tris(dibenzylideneacetone)dipalladium(0) (0.366 g, 0.4 mmol),1,3,5,7-tetramethyl-8-phenyl-2,4,6-trioxa-8-phosphaadamantane (0.351 g,1.2 mmol) and sodium carbonate (3.65 g, 34.4 mmol) were combined andsparged with nitrogen for 30 minutes. To this were addednitrogen-sparged 1,4-dioxane (40 mL) and water (10 mL) via syringe. Thereaction mixture was stirred at 60° C. for 5 hours. The reaction mixturewas cooled to ambient temperature and partitioned between ethyl acetateand water. The organic layer was washed with brine, treated with3-mercaptopropyl-functionalized silica gel for 20 minutes, dried overanhydrous magnesium sulfate, filtered through a plug of Celite andconcentrated. The residue was purified by flash chromatography (silicagel, 0 to 80% ethyl acetate in heptanes) to provide the title compoundas an impure mixture. The material was further purified by flashchromatography (silica gel, 0-25% ethyl acetate in dichloromethane) togive the title compound (3.73 g, 72%).

Example 135c4-(2-(2,6-dimethylphenoxy)-5-(methylsulfonyl)phenyl)-6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-2-carboxylicacid

To a solution of Example 135b (4.2 g, 6.47 mmol) in 1,4-dioxane (42 mL)was added lithium hydroxide (0.775 g, 32.4 mmol) and water (14 mL). Thereaction mixture was heated at 75° C. for 5 hours, cooled to ambienttemperature and acidified with 2 N aqueous hydrochloric acid. The solidwas collected by filtration, washed with water and dried overnight in avacuum oven at 70° C. to afford the title compound with 28 mole %1,4-dioxane as an excipient (3.08 g, 97%).

Example 135d2-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)-4-[2-(2,6-dimethylphenoxy)-5-(methylsulfonyl)phenyl]-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one

Example 135c (0.12 M in DMSO, 300 μL, 0.036mmol),1-ethyl-3-[3-(dimethylamino)propyl]-carbodiimide hydrochloride(0.15 M in DMSO, 300 μL, 0.044 mmol, 1.2 equivalents),1-hydroxybenzotriazole hydrate (0.15 M in DMSO, 300 μL, 0.044 mmol, 1.2equivalents) and N′-hydroxycyclopropanecarboximidamide (0.40 M in DMSO,137 μL, 0.055 mmol, 1.5 equivalents) were combined in a 4 mL vial,passed through a perfluoroalkoxy mixing tube (0.2 mm inner diameter),and loaded into an injection loop. The reaction segment was injectedinto a flow reactor (Hastelloy coil, 0.75 mm inner diameter, 1.8 mLinternal volume) set at 175° C., and passed through the reactor at 180μL min⁻¹ (10 minute residence time). Upon exiting the reactor, thereaction mixture was loaded directly into an injection loop and purifiedby preparative HPLC on a Phenomenex Luna C8(2) 5 μm 100 Å AXIA column(50 mm×21.2 mm). A gradient of acetonitrile (A) and 0.1% trifluoroaceticacid in water (B) was used, at a flow rate of 30 mL/min (0-0.5 min 5% A,0.5-6.5 min linear gradient 5-100% A, 6.5-8.5 min 100% A, 8.5-9.0 minlinear gradient 100-5% A, 9.0-10 min 5% A) to yield the title compound(8.72 mg, 45.2% yield). ¹H NMR (400 MHz, DMSO-d₆-D₂O) δ 7.99 (d, J=2.4Hz, 1H), 7.86 (dd, J=8.7, 2.4 Hz, 1H), 7.56 (s, 1H), 7.18 (d, J=6.6 Hz,2H), 7.13 (dd, J=8.7, 6.0 Hz, 1H), 7.05 (s, 1H), 6.62 (d, J=8.7 Hz, 1H),3.65 (s, 3H), 3.24 (s, 3H), 2.18 (ddd, J=13.2, 8.3, 4.9 Hz, 1H), 2.04(s, 6H), 1.12 (dt, J=8.1, 3.2 Hz, 2H), 0.98 (dt, J=6.9, 4.0 Hz, 2H). MS(APCI+) m/z 563.0 (M+MeOH+H)⁺.

Example 1362-(3-cyclohexyl-1,2,4-oxadiazol-5-yl)-4-[2-(2,6-dimethylphenoxy)-5-(methylsulfonyl)phenyl]-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one

Example 136 (9.58 mg, 46.0%) was prepared using the same proceduredescribed in Example 135d substitutingN′-hydroxycyclohexanecarboximidamide forN′-hydroxycyclopropanecarboximidamide. ¹H NMR (400 MHz, DMSO-d₆-D₂O) δ8.00 (d, J=2.4 Hz, 1H), 7.87 (dd, J=8.7, 2.4 Hz, 1H), 7.57 (s, 1H), 7.18(m, 2H), 7.13 (m, 1H), 7.08 (s, 1H), 6.63 (d, J=8.7 Hz, 1H), 3.65 (s,3H), 3.24 (s, 3H), 2.86 (tt, J=11.0, 3.6 Hz, 1H), 2.05 (s, 6H), 1.98 (m,2H), 1.77 (dt, J=11.7, 3.1 Hz, 2H), 1.68 (m, 1H), 1.54 (qd, J=12.4, 2.9Hz, 2H), 1.40 (qt, J=12.3, 3.0 Hz, 2H), 1.26 (m, 1H). MS (APCI+) m/z605.1 (M+MeOH+H)⁺.

Example 1374-[2-(2,6-dimethylphenoxy)-5-(methylsulfonyl)phenyl]-6-methyl-2-(3-phenyl-1,2,4-oxadiazol-5-yl)-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one

Example 137 (14.0 mg, 76.8%) was prepared using the same proceduredescribed in Example 135d substituting N′-hydroxybenzimidamide forN′-hydroxycyclopropanecarboximidamide. ¹H NMR (400 MHz, DMSO-d₆-D₂O) δ8.09 (m, 2H), 8.03 (d, J=2.4 Hz, 1H), 7.88 (dd, J=8.7, 2.4 Hz, 1H), 7.63(m, 3H), 7.59 (s, 1H), 7.19 (m, 3H), 7.12 (m, 1H), 6.65 (d, J=8.7 Hz,1H), 3.67 (s, 3H), 3.26 (s, 3H), 2.08 (s, 6H). MS (APCI+) m/z 599.1(M+MeOH+H)⁺.

Example 1384-[2-(2,6-dimethylphenoxy)-5-(methylsulfonyl)phenyl]-6-methyl-2-[3-(pyridin-3-yl)-1,2,4-oxadiazol-5-yl]-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one

Example 135c (0.21 M in DMSO, 200 μL, 0.043mmol),1-ethyl-3-[3-(dimethylamino)propyl]-carbodiimide hydrochloride(0.28 M in DMSO, 200 μL, 0.056 mmol, 1.3 equivalents),1-hydroxybenzotriazole hydrate (0.28 M in DMSO, 200 μL, 0.056 mmol, 1.3equivalents) and N′-hydroxynicotinimidamide (0.40 M in DMSO, 139 μL,0.055 mmol, 1.3 equivalents) were combined in a 4 mL vial, passedthrough a perfluoroalkoxy mixing tube (0.2 mm inner diameter), andloaded into an injection loop. The reaction segment was injected into aflow reactor (Hastelloy coil, 0.75 mm inner diameter, 1.8 mL internalvolume) set at 175° C., and passed through the reactor at 180 μL min⁻¹(10 minute residence time). Upon exiting the reactor, the reactionmixture was loaded directly into an injection loop and purified bypreparative HPLC on a Phenomenex Luna C8(2) 5 μm 100 Å AXIA column (50mm×21.2 mm). A gradient of acetonitrile (A) and 0.1% trifluoroaceticacid in water (B) was used, at a flow rate of 30 mL/min (0-0.5 min 5% A,0.5-6.5 min linear gradient 5-100% A, 6.5-8.5 min 100% A, 8.5-9.0 minlinear gradient 100-5% A, 9.0-10 min 5% A) to yield the title compound(6.33 mg, 21.7% yield). ¹H NMR (400 MHz, DMSO-d₆-D₂O) δ 9.23 (dd, J=2.1,0.7 Hz, 1H), 8.79 (dd, J=4.9, 1.7 Hz, 1H), 8.42 (dt, J=8.0, 2.0 Hz, 1H),8.01 (d, J=2.4 Hz, 1H), 7.85 (dd, J=8.7, 2.4 Hz, 1H), 7.63 (m, 1H), 7.50(s, 1H), 7.16 (m, 3H), 7.10 (m, 1H), 6.65 (d, J=8.7 Hz, 1H), 3.67 (s,3H), 3.21 (s, 3H), 2.07 (s, 6H). MS (APCI+) m/z 600.0 (M+MeOH+H)⁺.

Example 1394-[2-(2,6-dimethylphenoxy)-5-(methylsulfonyl)phenyl]-6-methyl-2-[3-(pyridin-2-yl)-1,2,4-oxadiazol-5-yl]-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one

Example 139 (5.89 mg, 20.1%) was prepared using the same proceduredescribed in Example 138 substituting N′-hydroxypicolinimidamide forN′-hydroxynicotinimidamide. ¹H NMR (400 MHz, DMSO-d₆-D₂O) δ 8.77 (ddd,J=4.7, 1.6, 0.9 Hz, 1H), 8.15 (m, 1H), 8.04 (td, J=7.8, 1.7 Hz, 1H),8.01 (d, J=2.4 Hz, 1H), 7.85 (dd, J=8.7, 2.4 Hz, 1H), 7.61 (ddd, J=7.6,4.8, 1.1 Hz, 1H), 7.50 (s, 1H), 7.16 (m, 3H), 7.10 (m, 1H), 6.65 (d,J=8.7 Hz, 1H), 3.66 (s, 3H), 3.21 (s, 3H), 2.07 (s, 6H). MS (APCI+) m/z600.0 (M+MeOH+H)⁺.

Example 1404-[2-(2,6-dimethylphenoxy)-5-(methylsulfonyl)phenyl]-6-methyl-2-[3-(pyrazin-2-yl)-1,2,4-oxadiazol-5-yl]-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one

Example 140 (2.58 mg, 8.8%) was prepared using the same proceduredescribed in Example 138 substitutingN′-hydroxypyrazine-2-carboximidamide for N′-hydroxynicotinimidamide. ¹HNMR (400 MHz, DMSO-d₆-D₂O) δ 9.31 (d, J=1.0 Hz, 1H), 8.85 (m, 2H), 8.01(d, J=2.3 Hz, 1H), 7.85 (dd, J=8.7, 2.3 Hz, 1H), 7.50 (s, 1H), 7.19 (s,1H), 7.16 (m, 2H), 7.11 (m, 1H), 6.65 (d, J=8.7 Hz, 1H), 3.67 (s, 3H),3.21 (s, 3H), 2.07 (s, 6H). MS (APCI+) m/z 601.0 (M+MeOH+H)⁺.

Example 1414-[2-(2,6-dimethylphenoxy)-5-(methylsulfonyl)phenyl]-6-methyl-2-[3-(tetrahydro-2H-pyran-4-yl)-1,2,4-oxadiazol-5-yl]-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one

Example 141 (7.2 mg, 24.3%) was prepared using the same proceduredescribed in Example 138, substitutingN′-hydroxytetrahydro-2H-pyran-4-carboximidamide forN′-hydroxynicotinimidamide. ¹H NMR (400 MHz, DMSO-d₆-D₂O) δ 7.99 (d,J=2.4 Hz, 1H), 7.84 (dd, J=8.7, 2.4 Hz, 1H), 7.47 (s, 1H), 7.16 (m, 2H),7.11 (m, 1H), 7.05 (s, 1H), 6.63 (d, J=8.7 Hz, 1H), 3.91 (dt, J=11.4,3.7 Hz, 2H), 3.65 (s, 3H), 3.51 (td, J=11.3, 2.5 Hz, 2H), 3.20 (s, 3H),3.15 (m, 1H), 2.05 (s, 6H), 1.96 (m, 2H), 1.81 (m, 2H). MS (APCI+) m/z607.1 (M+MeOH+H)⁺.

Example 1424-[2-(2,6-dimethylphenoxy)-5-(methylsulfonyl)phenyl]-6-methyl-2-[3-(1,3-thiazol-4-yl)-1,2,4-oxadiazol-5-yl]-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one

Example 142 (5.5 mg, 18.6%) was prepared using the same proceduredescribed in Example 138 substitutingN′-hydroxythiazole-4-carboximidamide for N′-hydroxynicotinimidamide. ¹HNMR (400 MHz, DMSO-d₆-D₂O) δ 9.26 (d, J=2.0 Hz, 1H), 8.46 (d, J=2.0 Hz,1H), 8.01 (d, J=2.4 Hz, 1H), 7.85 (dd, J=8.7, 2.4 Hz, 1H), 7.49 (s, 1H),7.15 (m, 3H), 7.11 (m, 1H), 6.65 (d, J=8.7 Hz, 1H), 3.66 (s, 3H), 3.21(s, 3H), 2.06 (s, 6H). MS (APCI+) m/z 606.0 (M+MeOH+H)⁺.

Example 143N-[2-(diethylamino)-2-methylpropyl]-4-[2-(2,6-dimethylphenoxy)-5-(methylsulfonyl)phenyl]-6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-2-carboxamide

To a solution of Example 135c (74.5 mg, 0.160 mmol) in dichloromethane(4 mL) at 0° C. was added 1-chloro-N,N,2-trimethyl-1-propenylamine(Ghosez's reagent) (55 μL, 0.416 mmol). The mixture was stirred for 60minutes. 2-(Diethylamino)-2-methylpropylamine dihydrochloride, (108.06mg, 0.547 mmol) in pyridine (0.5 mL, 6.18 mmol)/tetrahydrofuran (2 mL)was added, and the mixture stirred at ambient temperature overnight. Themixture was diluted with dichloromethane and extracted with pH7 buffer.After filtration and solvent removal, the crude product was purified bypreparative HPLC on a Phenomenex Luna C8(2) 5 μm 100 Å AXIA column (30mm×75 mm). A gradient of acetonitrile (A) and 0.1% trifluoroacetic acidin water (B) was used, at a flow rate of 30 mL/minutes (0-0.5 minutes 5%A, 0.5-6.5 minutes linear gradient 5-100% A, 6.5-8.5 minutes 100% A,8.5-9.0 minutes linear gradient 100-5% A, 9.0-10 minutes 5% A). Sampleswere injected in 1.5 mL DMSO:methanol (1:1). A custom purificationsystem was used, consisting of the following modules: Waters LC4000preparative pump; Waters 996 diode-array detector; Waters 717+autosampler; Waters SAT/IN module, Alltech Varex III evaporativelight-scattering detector; Gilson 506C interface box; and two GilsonFC204 fraction collectors. The system was controlled using WatersMillennium32 software, automated using an Abbott developed Visual Basicapplication for fraction collector control and fraction tracking.Fractions were collected based upon UV signal threshold and selectedfractions subsequently analyzed by flow injection analysis massspectrometry using positive APCI ionization on a Finnigan LCQ using70:30 methanol:10 mM NH₄OH(aq) at a flow rate of 0.8 mL/minutes.Loop-injection mass spectra were acquired using a Finnigan LCQ runningLCQ Navigator 1.2 software and a Gilson 215 liquid handler for fractioninjection controlled by an Abbott developed Visual Basic application.Purification as described provided the title compound as atrifluoroacetic acid salt. ¹H NMR (400 MHz, DMSO-d₆) δ 7.96 (d, J=2.4Hz, 1H), 7.84 (dd, J=8.7, 2.4 Hz, 1H), 7.43 (s, 1H), 7.25-7.05 (m, 3H),6.94 (s, 1H), 6.63 (d, J=8.6 Hz, 1H), 3.66 (s, 2H), 3.64 (s, 3H), 3.48(m, 4H), 3.20 (s, 3H), 2.03 (s, 6H), 1.40 (s, 6H), 1.33 (t, J=7.3 Hz,6H). MS (APCI+) m/z 592.1 (M+H)⁺.

Example 144N-[4-(diethylamino)butyl]-4-[2-(2,6-dimethylphenoxy)-5-(methylsulfonyl)phenyl]-6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-2-carboxamide

The trifluoroacetic acid salt of Example 144 was prepared according tothe procedure used for the preparation of Example 143, substituting4-(diethylamino)butylamine for 2-(diethylamino)-2-methylpropylaminedihydrochloride. ¹H NMR (400 MHz, DMSO-d₆) δ 7.96 (d, J=2.4 Hz, 1H),7.83 (dd, J=8.8, 2.4 Hz, 1H), 7.42 (s, 1H), 7.19-7.07 (m, 3H), 6.87 (s,1H), 6.63 (d, J=8.7 Hz, 1H), 3.63 (s, 3H), 3.32 (m, 2H), 3.19 (s, 3H),3.15-3.03 (m, 6H), 2.03 (s, 6H), 1.76-1.55 (m, 4H), 1.22 (t, J=7.3 Hz,6H). MS (APCI+) m/z 592.1 (M+H)⁺.

Example 145N-ethyl-4-{5-(ethylsulfonyl)-2-[2-methyl-6-(1H-pyrazol-1-ylmethyl)phenoxy]phenyl}-6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-2-carboxamideExample 145a 2-(2-bromo-4-(ethylsulfonyl)phenoxy)-3-methylbenzaldehyde

A mixture of 2-bromo-4-(ethylsulfonyl)-1-fluorobenzene (1.20 g, 4.5mmol), 2-hydroxy-3-methylbenzaldehyde (1.225 g, 9.00 mmol), and cesiumcarbonate (2.93 g, 9.00 mmol) in DMSO (10 mL) was heated at 110° C.overnight. Aqueous workup followed by flash chromatography (silica gel,heptane/ethyl acetate gradient) afforded the title compound (1.62 g,4.23 mmol, 94% yield)

Example 145b(2-(2-bromo-4-(ethylsulfonyl)phenoxy)-3-methylphenyl)methanol

To a solution of Example 145a (3 g, 7.83 mmol) in tetrahydrofuran (30mL) was added sodium borohydride (0.444 g, 11.7 mmol) portionwise. Themixture was stirred at ambient temperature overnight. The reactionmixture was then quenched with water and extracted with ethyl acetate.The organic phase was dried over anhydrous sodium sulfate, filtered, andconcentrated under vacuum. Purification of the residue by flashchromatography (silica gel, 0-50% (ethyl acetate/petroleum ether)afforded the title compound (2.5 g, 6.49 mmol, 83% yield).

Example 145c2-(2-bromo-4-(ethylsulfonyl)phenoxy)-1-(bromomethyl)-3-methylbenzene

To a solution of Example 145b (700 mg, 1.817 mmol) in dichloromethane (5mL) was added phosphorus tribromide (0.188 mL, 1.999 mmol). The mixturewas stirred at ambient temperature overnight. The mixture was thenconcentrated under vacuum to afford the crude product, which was useddirectly in next step without purification.

Example 145d1-(2-(2-bromo-4-(ethylsulfonyl)phenoxy)-3-methylbenzyl)-1H-pyrazole

Example 145c (150 mg, 0.335 mmol), 1H-pyrazole (68.4 mg, 1.004 mmol),and dimethylformamide (3 mL) were placed in a 5 mL vial. The mixture wasstirred at 50° C. overnight. The mixture was cooled to ambienttemperature and concentrated under reduced pressure. The residue waspurified by flash chromatography (silica gel, 0-50% ethylacetate/petroleum ether) to afford the title compound (120 mg, 0.276mmol, 82% yield).

Example 145e4-bromo-6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-2-carboxylicacid

Example 114c, (7.25 g, 24.24 mmol) in tetrahydrofuran (70 mL) andethanol (140 mL) was heated at 75° C. to dissolution and then cooled to35° C. To this solution was added 1M LiOH solution (97 mL). The reactionmixture was heated at 75° C. for 2 hours, start. The reaction mixturewas cooled to ambient temperature, and 1N HCl (100 mL) was addedfollowed by water (300 mL). The resulting suspension was allowed to stirat ambient temperature overnight. The resulting precipitate wascollected by vacuum filtration, rinsed with water, and dried in vacuo at50° C. for 24 hours to provide the title compound (6.41 g, 98% yield).

Example 145f4-bromo-N-ethyl-6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-2-carboxamide

A mixture of Example 145e (5.4 g, 20 mmol) in dimethyl sulfoxide (100mL) was treated with2-(3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)-1,1,3,3-tetramethylisouroniumhexafluorophosphate(V) (8.33 g, 21.91 mmol) andN-ethyl-N-isopropylpropan-2-amine (10.5 mL, 60.1 mmol) and stirred for 5minutes. Ethylamine solution (2 M in tetrahydrofuran) (11 mL, 22.00mmol) was added and stirring was continued at ambient temperature for 6hours and 40 minutes. The reaction mixture was then diluted with 600 mLof water and stirred overnight at ambient temperature. The solid wascollected by vacuum filtration and rinsed with 1 L of water. The solidwas dried by pulling air through for an hour and then further dried in avacuum oven at 70° C. to give the title compound (5.54 g, 93% yield).

Example 145gN-ethyl-6-methyl-7-oxo-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-2-carboxamide

A mixture of Example 145f (2.504 g, 8.4 mmol),4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (3.41 g,13.44 mmol), 2-(dicyclohexylphosphino)-2′,4′,6′-triisopropylbiphenyl(0.521 g, 1.092 mmol), tris(dibenzylideneacetone)dipalladium(0) (0.308g, 0.336 mmol) and potassium acetate (2.473 g, 25.2 mmol) was purgedwith nitrogen for 15 minutes. Dioxane (42 mL, thoroughly degassed withnitrogen) was transferred into the flask and the mixture was purged withnitrogen for another 5 minutes. The reaction mixture was stirred at 80°C. for 16 hours. The reaction mixture was then partitioned with ethylacetate and water. The organic layer was washed with saturated aqueoussodium chloride, dried with anhydrous sodium sulfate, treated with3-mercaptopropyl functionalized silica gel, filtered and evaporated. Theresidue was purified by flash chromatography (silica gel, 0%-100% ethylacetate in dichloromethane) to give a solid. This solid was trituratedwith heptanes to give the title compound (1.89 g, 65% yield).

Example 145hN-ethyl-4-{5-(ethylsulfonyl)-2-[2-methyl-6-(1H-pyrazol-1-ylmethyl)phenoxy]phenyl}-6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-2-carboxamide

A mixture of Example 145d 1 (20 mg, 0.046 mmol), Example 145g (17.45 mg,0.051 mmol), sodium carbonate (19.48 mg, 0.184 mmol),tris(dibenzylideneacetone)dipalladium(0) (4.21 mg, 4.59 μmol),1,3,5,7-tetramethyl-8-phenyl-2,4,6-trioxa-8-phosphaadamantane (1.343 mg,4.59 μmol), and tetrahydrofuran (4 mL) and water, (1 mL) was degassedthoroughly under nitrogen, and then was stirred at 60° C. overnight. Thereaction mixture was cooled to ambient temperature and the solventremoved under reduced pressure. The residue was purified by reversephase HPLC (C18, 5-95% acetonitrile in 0.05% TFA/water) to provide thetitle compound. ¹H NMR (300 MHz, CD₃OD) δ 8.32 (d, J=2.4 Hz, 1H), 8.05(dd, J=8.7, 2.4 Hz, 1H), 7.80 (s, 1H), 7.70 (s, 1H), 7.64 (d, J=2.5 Hz,2H), 7.54 (t, J=7.5 Hz, 1H), 7.40 (d, J=7.5 Hz, 1H), 7.29 (s, 1H), 6.92(d, J=8.7 Hz, 1H), 6.46 (s, 1H), 5.53 (d, J=11.2 Hz, 2H), 4.03 (s, 3H),3.70 (q, J=7.3 Hz, 1H), 3.61-3.51 (m, 5H), 2.37 (s, 3H), 1.58 (t, J=7.3Hz, 3H), 1.50 (t, J=7.3 Hz, 3H). MS (ESI+) m/z 574.3 (M+H)⁺.

Example 146N-ethyl-4-{5-(ethylsulfonyl)-2-[2-methyl-6-(morpholin-4-ylmethyl)phenoxy]phenyl}-6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-2-carboxamideExample 146aN-ethyl-4-(5-(ethylsulfonyl)-2-(2-formyl-6-methylphenoxy)phenyl)-6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-2-carboxamide

Example 145g (500 mg, 1.304 mmol),tris(dibenzylideneacetone)dipalladium(0) (119 mg, 0.130 mmol), sodiumcarbonate (553 mg, 5.21 mmol),1,3,5,7-tetramethyl-8-phenyl-2,4,6-trioxa-8-phosphaadamantane (38.1 mg,0.130 mmol), and Example 145a (555 mg, 1.30 mmol) were combined andsparged with argon for 15 minutes. Meanwhile a solution oftetrahydrofuran (20 mL) and water (5 mL) was sparged with nitrogen for15 minutes and transferred by syringe into the reaction vessel underargon. The mixture was stirred for 4 hours under argon at 60° C., cooledto ambient temperature, and partitioned between ethyl acetate and water.The organic layer was washed with saturated aqueous sodium chloride,dried over anhydrous sodium sulfate, treated with 3-mercaptopropylfunctionalized silica gel, filtered and concentrated. Purification bychromatography (silica gel, 20-70% 3:1 ethyl acetate/ethanol inheptanes) provided the title compound (530 mg, 74% yield).

Example 146bN-ethyl-4-{5-(ethylsulfonyl)-2-[2-methyl-6-(morpholin-4-ylmethyl)phenoxy]phenyl}-6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-2-carboxamide

A mixture of Example 146a (140 mg, 0.228 mmol), sodiumtriacetoxyhydroborate (145 mg, 0.684 mmol), morpholine (0.060 g, 0.68mmol), and two drops of acetic acid in 1,2 dichloroethane (20 mL) wasstirred at ambient temperature overnight. The solvent was removed underreduced pressure, and the residue was purified by reverse phase HPLC(C18, 0-100% acetonitrile in 0.1% TFA/water) to provide the titlecompound (54.5 mg, 40% yield). ¹H NMR (300 MHz, DMSO-d₆) δ 12.4 (bs,1H), 8.35 (bs, 1H), 7.91 (d, J=2.4 Hz, 1H), 7.78 (dd, J=8.8, 2.4 Hz,1H), 7.46 (s, 1H), 7.28 (d, J=7.6 Hz, 2H), 7.19 (dd, J=8.0, 6.8 Hz, 1H),6.81 (s, 1H), 6.58 (d, J=8.8 Hz, 1H), 3.61 (s, 3H), 3.30 (m, 8H), 3.25(d, J=7.2 Hz, 1H), 2.14 (bs, 4H), 2.06 (s, 3H), 1.14 (t, J=7.2 Hz, 3H),1.12 (t, J=7.2 Hz, 3H). MS (ESI+) m/z 593.3 (M+H)⁺.

Example 147N-ethyl-4-{5-(ethylsulfonyl)-2-[2-methyl-6-(piperidin-1-ylmethyl)phenoxy]phenyl}-6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-2-carboxamide

Example 147 was prepared according to the procedure described for thepreparation of Example 146b, substituting peperidine for morpholine. ¹HNMR (400 MHz, DMSO) δ 12.32 (s, 1H), 8.35 (t, J=5.2 Hz, 1H), 7.90 (d,J=2.4 Hz, 1H), 7.77 (dd, J=8.7, 2.4 Hz, 1H), 7.45 (s, 1H), 7.26 (d,J=7.6 Hz, 2H), 7.21-7.15 (m, 1H), 6.81 (s, 1H), 6.57 (d, J=8.7 Hz, 1H),3.61 (s, 4H), 3.32 (s, 5H), 3.32-3.20 (m, 6H), 3.03 (d, J=13.0 Hz, 1H),2.08 (s, 3H), 2.06 (s, 5H), 1.21 (s, 7H), 1.13 (dd, J=13.5, 7.2 Hz, 8H).MS (ESI+) m/z 591.4 (M+H)⁺.

Example 148N-ethyl-4-{5-(ethylsulfonyl)-2-[2-methyl-6-(2-phenylethyl)phenoxy]phenyl}-6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-2-carboxamideExample 148a ethyl4-(5-(ethylsulfonyl)-2-(2-formyl-6-methylphenoxy)phenyl)-6-methyl-7-oxo-1-tosyl-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-2-carboxylate

To a degassed solution of Example 114d (914 mg, 1.826 mmol) in1,4-dioxane (8 mL) and water (2 mL) was added Example 145a (700 mg,1.826 mmol), tris(dibenzylideneacetone)dipalladium(0) (50.2 mg, 0.055mmol), 1,3,5,7-tetramethyl-8-phenyl-2,4,6-trioxa-8-phosphaadamantane(53.4 mg, 0.183 mmol), and potassium phosphate (1163 mg, 5.48 mmol). Themixture was stirred for 4 hours under nitrogen at 60° C. The mixture wascooled and partitioned between ethyl acetate and water. The organiclayer was washed with saturated aqueous sodium chloride, dried overanhydrous sodium sulfate, treated with Celite, filtered andconcentrated. The residue was purified by chromatography (silica gel,0-100% ethyl acetate in heptanes) to provide the title compound (350 mg,0.517 mmol, 28.3% yield).

Example 148b ethyl4-(5-(ethylsulfonyl)-2-(2-methyl-6-styrylphenoxy)phenyl)-6-methyl-7-oxo-1-tosyl-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-2-carboxylate(E/Z mixture)

Under nitrogen to a solution of benzyltriphenylphosphonium chloride (345mg, 0.887 mmol) in tetrahydrofuran (6 mL) was added sodiumbis(trimethylsilyl)amide (0.975 mL, 0.975 mmol) dropwise at −30° C. Themixture was stirred for 1 hour at 20° C. A solution of Example 148a (300mg, 0.443 mmol) in tetrahydrofuran (0.5 mL) was added dropwise to themixture at −78° C. The mixture was allowed to warm to 20° C. and stirredfor 2 hours. The mixture was partitioned between ethyl acetate andwater. The organic layer was washed with saturated aqueous sodiumchloride, dried over anhydrous sodium sulfate, filtered andconcentrated. The residue was purified by chromatography (silica gel,0-50% ethyl acetate in heptane gradient) to provide the title compound(310 mg, 0.407 mmol, 92% yield).

Example 148c4-(5-(ethylsulfonyl)-2-(2-methyl-6-styrylphenoxy)phenyl)-6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-2-carboxylicacid (E/Z mixture)

To a solution of Example 148b (300 mg, 0.400 mmol) in a mixture of1,4-dioxane (4 mL) and water (3 mL) was added lithium hydroxide hydrate(168 mg, 4.00 mmol). The reaction mixture was heated at 85° C. for 1.5hours, cooled, diluted with ethyl acetate and the pH was adjusted to 2by addition of concentrated hydrochloric acid. The mixture was extractedwith ethyl acetate. The organic layer was washed with saturated sodiumchloride solution, dried over anhydrous sodium sulfate, filtered andconcentrated to afford the title compound (185 mg, 0.325 mmol, 81%yield).

Example 148dN-ethyl-4-(5-(ethylsulfonyl)-2-(2-methyl-6-styrylphenoxy)phenyl)-6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-2-carboxamide(E/Z mixture)

Under nitrogen, to a solution of Example 148c (180 mg, 0.317 mmol) inDMSO (10 mL) was addedO-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate (144 mg, 0.380 mmol), ethanamine (0.317 mL, 0.633mmol) and diisopropylethylamine (0.111 mL, 0.633 mmol).The mixture wasstirred for 12 hours at 25° C. The mixture was partitioned between ethylacetate and water. The organic layer was washed with saturated brine,dried over anhydrous sodium sulfate, filtered and concentrated. Thecrude product was purified by Prep-HPLC with the following conditions:Column:Waters HSS C18, 2.1*50 mm, 1.8 m; Mobile Phase A:Water/0.05% TFA,Mobile Phase B: acetonitrile/0.05% TFA, Flow rate: 0.7 mL/min;Gradient:5% B to 95% B in 2.0 min, hold 0.6 min; 254 nm to provide(Z)—N-ethyl-4-(5-(ethylsulfonyl)-2-(2-methyl-6-styrylphenoxy)phenyl)-6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-2-carboxamide(58.3 mg, 0.098 mmol, 31% yield) and(E)-N-ethyl-4-(5-(ethylsulfonyl)-2-(2-methyl-6-styrylphenoxy)phenyl)-6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-2-carboxamide(2.6 mg, 4.36 μmol, 1.4% yield).

Example 148eN-ethyl-4-{5-(ethylsulfonyl)-2-[2-methyl-6-(2-phenylethyl)phenoxy]phenyl}-6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-2-carboxamide

Under nitrogen, to a solution of Example 148d (5 mg, 8.39 μmol) inmethanol (1 mL) was added 10% Pd/C (0.179 mg, 1.679 μmol).The mixturewas charged with hydrogen. The mixture was stirred for 1 hour at 20° C.under hydrogen (2 atmosphere). The solids were removed by filtration.The filtrate was concentrated under reduced pressure to obtain the titlecompound (5 mg, 100% yield) as a light-yellow solid. ¹H NMR (300 MHz,CD₃OD) δ 8.32 (d, J=2.4 Hz, 1H), 8.05 (dd, J=8.7, 2.4 Hz, 1H), 7.80 (s,1H), 7.70 (s, 1H), 7.64 (d, J=2.5 Hz, 2H), 7.54 (t, J=7.5 Hz, 1H), 7.40(d, J=7.5 Hz, 1H), 7.29 (s, 1H), 6.92 (d, J=8.7 Hz, 1H), 6.46 (s, 1H),5.53 (d, J=11.2 Hz, 2H), 4.03 (s, 3H), 3.70 (q, J=7.3 Hz, 1H), 3.61-3.51(m, 5H), 2.37 (s, 3H), 2.04-2.04 (m, 1H), 2.02-2.01 (m, 1H), 1.58 (t,J=7.3 Hz, 3H), 1.50 (t, J=7.3 Hz, 4H). MS (ESI+) m/z 598.2 (M+H)⁺.

Example 1494-[2-(cyclohexyloxy)-5-(ethylsulfonyl)phenyl]-6-methyl-2-[1-(piperidin-4-yl)-1H-pyrazol-4-yl]-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-oneExample 149a tert-butyl4-(4-(4-bromo-6-methyl-7-oxo-1-tosyl-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-2-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylate

Example 63c (1.32 g, 2.60 mmol), sodium carbonate (0.964 g, 9.10 mmol),tris(dibenzylideneacetone)dipalladium (0.071 g, 0.078 mmol) and1,3,5,7-tetramethyl-6-phenyl-2,4,8-trioxa-6-phosphaadamantane (0.068 g,0.23 mmol) were combined and purged with nitrogen for 15 minutes. Amixture of tetrahydrofuran (16 mL) and water (4 mL) was purged withnitrogen for 15 minutes and transferred to the reaction vessel. To thisreaction mixture was added tert-butyl4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylate(0.981 g, 2.60 mmol) in tetrahydrofuran (4 mL). The reaction mixture waspurged with nitrogen for another 5 minutes, heated at 35° C. for 20hours, cooled to ambient temperature, and partitioned with ethyl acetateand water. The organic layer was washed with saturated aqueous sodiumchloride, dried with anhydrous sodium sulfate, treated with3-mercaptopropyl functionalized silica gel, filtered, and concentrated.The residue was purified by flash chromatography (silica gel, 1-2%methanol in dichloromethane) and followed by trituration with heptanesto give the title compound (1.29 g, 79%).

Example 149b tert-butyl4-(4-(6-methyl-7-oxo-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-tosyl-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-2-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylate

Example 149a (1.26 g, 2.00 mmol),4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (1.52 g,6.00 mmol), 2-(dicyclohexylphosphino)-2′,4′,6′-triisopropylbiphenyl (86mg, 0.18 mmol), tris(dibenzylideneacetone)dipalladium (55 mg, 0.060mmol) and potassium acetate (589 mg, 6.00 mmol) were combined and purgedwith nitrogen for 15 minutes. Dioxane (20 mL) was purged with nitrogenfor 15 minutes and transferred to the reaction vessel. The reactionmixture was heated at 70° C. for 16 hours, cooled to ambienttemperature, and partitioned with ethyl acetate and water. The organiclayer was washed with saturated aqueous sodium chloride, dried withanhydrous sodium sulfate, treated with 3-mercaptopropyl functionalizedsilica gel, filtered, and concentrated. The residue was purified byflash chromatography (silica gel, 20-40% 3:1 ethyl acetate/ethanol inheptanes) and followed by trituration with heptanes to give the titlecompound (545 mg, 40%).

Example 149c 2-bromo-1-(cyclohexyloxy)-4-(ethylsulfonyl)benzene

To a solution of cyclohexanol (3.00 g, 30.0 mmol) in tetrahydrofuran (60mL) was added 60% sodium hydride (1.32 g, 33.0 mmol) portionwise. Thereaction mixture was stirred at ambient temperature for 10 minutes. Tothis reaction mixture was added Example 16i (4.01 g, 15.0 mmol). Thereaction mixture was heated at 60° C. for 6 hours, cooled to ambienttemperature, and partitioned with ethyl acetate and water. The organiclayer was washed with saturated aqueous sodium chloride, dried withanhydrous sodium sulfate, filtered and concentrated. The residue waspurified by flash chromatography (silica gel, 20-40% ethyl acetate inheptanes) and dried by vacuum to give the title compound (5.21 g, 100%).

Example 149d tert-butyl4-(4-(4-(2-(cyclohexyloxy)-5-(ethylsulfonyl)phenyl)-6-methyl-7-oxo-1-tosyl-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-2-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylate

Example 149b (500 mg, 0.738 mmol), Example 149c (256 mg, 0.738 mmol),sodium carbonate (274 mg, 2.58 mmol),tris(dibenzylideneacetone)dipalladium (20 mg, 0.022 mmol) and1,3,5,7-tetramethyl-6-phenyl-2,4,8-trioxa-6-phosphaadamantane (19.4 mg,0.066 mmol) were combined and purged with nitrogen for 15 minutes. Amixture of tetrahydrofuran (6 mL) and water (1.5 mL) was purged withnitrogen for 15 minutes and transferred to the reaction vessel. Thereaction mixture was heated at 60° C. for 3 hours, cooled to ambienttemperature, and partitioned with ethyl acetate and water. The organiclayer was washed with saturated aqueous sodium chloride, dried withanhydrous sodium sulfate, treated with 3-mercaptopropyl functionalizedsilica gel, filtered, and concentrated. The residue was purified byflash chromatography (silica gel, 20-50% 3:1 ethyl acetate/ethanol inheptanes) and followed by trituration with heptanes to give the titlecompound (480 mg, 80%).

Example 149e tert-butyl4-(4-(4-(2-(cyclohexyloxy)-5-(ethylsulfonyl)phenyl)-6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-2-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylate

Example 149d (478 mg, 0.584 mmol) and lithium hydroxide (140 mg, 5.84mmol) were combined in the mixture of dioxane (12 mL) and water (4 mL).The reaction mixture was heated at 70° C. for 16 hours, cooled toambient temperature, diluted with water, filtered, washed with water anddried to give the title compound (318 mg, 82%).

Example 149f4-[2-(cyclohexyloxy)-5-(ethylsulfonyl)phenyl]-6-methyl-2-[1-(piperidin-4-yl)-1H-pyrazol-4-yl]-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one

To a solution of Example 149e (309 mg, 0.465 mmol) in dichloromethane(3.0 mL) was added trifluoroacetic acid (3.0 mL, 39 mmol). The reactionmixture was stirred at ambient temperature for 30 minutes, concentrated,azeotroped with dichloromethane twice, and triturated with ethyl etherto give the title compound (315 mg, 100%) as the trifluoroacetic acidsalt. ¹H NMR (400 MHz, DMSO-d₆) δ 12.11 (s, 1H), 8.78-8.64 (m, 1H),8.52-8.38 (m, 1H), 8.32 (s, 1H), 8.01 (s, 1H), 7.80 (dd, J=8.6, 2.2 Hz,1H), 7.76 (d, J=2.1 Hz, 1H), 7.38 (d, J=8.8 Hz, 1H), 7.29 (s, 1H), 6.29(d, J=1.8 Hz, 1H), 4.67-4.41 (m, 2H), 3.56 (s, 3H), 3.44-3.36 (m, 2H),3.27 (q, J=7.3 Hz, 2H), 3.15-3.03 (m, 2H), 2.26-2.17 (m, 2H), 2.14-2.01(m, 2H), 1.91-1.79 (m, 2H), 1.58-1.47 (m, 2H), 1.45-1.26 (m, 5H),1.22-1.08 (m, 4H). (ESI+) m/z 564 (M+H)⁺.

Example 150N-ethyl-4-{5-(ethylsulfonyl)-2-[2-(1H-imidazol-1-ylmethyl)-6-methylphenoxy]phenyl}-6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-2-carboxamideExample 150a1-(2-(2-bromo-4-(ethylsulfonyl)phenoxy)-3-methylbenzyl)-1H-imidazole

Example 150a was prepared according to the procedure described for thepreparation of Example 145d, substituting 1H-imidazole for 1H-pyrazole.

Example 150bN-ethyl-4-{5-(ethylsulfonyl)-2-[2-(1H-imidazol-1-ylmethyl)-6-methylphenoxy]phenyl}-6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-2-carboxamide

Example 150b was prepared according to the procedure described for thepreparation of Example 145h, substituting Example 150a for Example 145d.¹H NMR (400 MHz, CD₃OD) δ 8.31 (d, J=2.3 Hz, 1H), 8.03 (dd, J=8.7, 2.3Hz, 1H), 7.73 (s, 1H), 7.67 (m, 2H), 7.56 (t, J=7.5 Hz, 1H), 7.51 (d,J=6.0 Hz, 1H), 7.22 (s, 1H), 7.08 (d, J=6.0 Hz, 2H), 6.87 (d, J=8.7 Hz,1H), 5.35 (m, 2H), 4.00 (s, 3H), 3.68 (dd, J=14.7, 7.3 Hz, 3H), 3.55 (q,J=7.4 Hz, 3H), 2.41 (s, 3H), 1.58 (t, J=7.4 Hz, 3H), 1.49 (t, J=7.3 Hz,3H). MS (ESI+) m/z 575.2 (M+H)⁺.

Example 151N-ethyl-4-[5-(ethylsulfonyl)-2-{2-methyl-6-[(2-oxopyrrolidin-1-yl)methyl]phenoxy}phenyl]-6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-2-carboxamideExample 151a1-(2-(2-bromo-4-(ethylsulfonyl)phenoxy)-3-methylbenzyl)pyrrolidin-2-one

To a solution of Example 145c (300 mg, 0.669 mmol) and pyrrolidin-2-one(171 mg, 2.008 mmol) in tetrahydrofuran (10 mL) at 0° C. was addedsodium hydride (56.2 mg, 2.343 mmol). The mixture was stirred at ambienttemperature overnight. The reaction mixture was partitioned betweenethyl acetate and water, and the organic layer separated and dried overanhydrous sodium sulfate, filtered, and concentrated. The residue waspurified by flash chromatography (silica gel, 0-10%methanol/dichloromethane gradient) to provide the title compound (150mg, 49.5% yield).

Example 151bN-ethyl-4-[5-(ethylsulfonyl)-2-{2-methyl-6-[(2-oxopyrrolidin-1-yl)methyl]phenoxy}phenyl]-6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-2-carboxamide

Example 151b was prepared according to the procedure described for thepreparation of Example 145h, substituting Example 151a for Example 145d.¹H NMR (400 MHz, CD₃OD) δ 8.32 (d, J=2.3 Hz, 1H), 8.13 (dd, J=8.6, 2.3Hz, 1H), 7.95 (s, 1H), 7.56 (m, 3H), 7.29 (s, 1H), 6.96 (d, J=8.8 Hz,1H), 5.07 (m, 2H), 4.05 (s, 3H), 3.71 (q, J=7.2 Hz, 3H), 3.57 (q, J=7.4Hz, 3H), 3.45 (t, J=7.1 Hz, 2H), 2.52 (m, 1H), 2.33 (s, 3H), 2.16 (m,2H), 1.58 (t, J=7.4 Hz, 4H), 1.53 (t, J=7.3 Hz, 3H). MS (ESI+) m/z 562.2(M-28)⁺.

Example 1524-[2-{2-[(1,1-dioxido-1,2-thiazolidin-2-yl)methyl]-6-methylphenoxy}-5-(ethylsulfonyl)phenyl]-N-ethyl-6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-2-carboxamideExample 152a2-(2-(2-bromo-4-(ethylsulfonyl)phenoxy)-3-methylbenzyl)isothiazolidine1,1-dioxide

Example 152a was prepared according to the procedure described for thepreparation of Example 151a, substituting isothiazolidine 1,1-dioxidefor pyrrolidin-2-one.

Example 152b4-[2-{2-[(1,1-dioxido-1,2-thiazolidin-2-yl)methyl]-6-methylphenoxy}-5-(ethylsulfonyl)phenyl]-N-ethyl-6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-2-carboxamide

Example 152b was prepared according to the procedure described for thepreparation of Example 145h, substituting Example 152a for Example 145d.¹H NMR (400 MHz, CD₃OD) δ 8.28 (d, J=2.3 Hz, 1H), 8.09 (dd, J=8.7, 2.4Hz, 1H), 7.83 (s, 1H), 7.61 (d, J=7.7 Hz, 1H), 7.57 (d, J=6.2 Hz, 1H),7.50 (t, J=7.6 Hz, 1H), 7.24 (s, 1H), 6.96 (d, J=8.7 Hz, 1H), 4.48 (m,1H), 4.09 (m, 1H), 4.01 (s, 3H), 3.69 (m, 2H), 3.53 (q, J=7.4 Hz, 2H),3.25 (m, 4H), 2.42 (m, 2H), 2.30 (s, 3H), 1.54 (t, J=7.4 Hz, 3H), 1.50(t, J=7.3 Hz, 3H). MS (ESI+) m/z 627.4 (M+H)⁺.

Example 1534-[2-(2,6-dimethylphenoxy)-4-{[2-(methylamino)-2-oxoethyl](pyridin-2-ylmethyl)carbamoyl}phenyl]-N-ethyl-6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-2-carboxamideExample 153a Methyl 3-(2,6-dimethylphenoxy)-4-nitrobenzoate

A mixture of methyl 3-fluoro-4-nitrobenzoate (70 g, 352mmol),2,6-dimethylphenol (42.9 g, 352 mmol) and potassium carbonate(58.3 g, 422 mmol) in dimethylsulfoxide (500 mL) was heated at 120° C.for 4 hours. The reaction mixture was quenched with water and extractedtwice with ethyl acetate. The combined organic layers were washed withbrine, dried with anhydrous magnesium sulfate, filtered andconcentrated. The residue was purified by flash chromatography (silicagel, 0-100% ethyl acetate in heptane) to afford 73 g (69%) of the titlecompound.

Example 153b Methyl 4-amino-3-(2,6-dimethylphenoxy)benzoate

To Example 153a (30 g, 100 mmol) in tetrahydrofuran (800 mL) was addedpalladium on carbon (5.30 g, 49.8 mmol). The reaction mixture wasstirred for 40 hours at 60 psi hydrogen atmosphere and 40° C. Themixture was filtered through a nylon membrane, and the filtrate wasconcentrated to afford 25 g (93%) of the title compound.

Example 153c Methyl 3-(2,6-dimethylphenoxy)-4-iodobenzoate

Example 153b (25 g, 92 mmol) in tetrahydrofuran (200 mL) was treatedwith concentrated hydrochloric acid (140 mL, 1694 mmol) at 0° C. Thereaction mixture was stirred at 0° C. for 10 minutes. To this solutionwas added a solution sodium nitrite (7.63 g, 111 mmol) in water (20 mL).The reaction mixture was stirred at 0° C. for 1 hour. To this solutionwas added a solution of potassium iodide (30.6 g, 184 mmol) in water (50mL). The reaction mixture was stirred for 2 hours at 10° C. The reactionmixture was partitioned between water and ethyl acetate. The aqueouslayer was extracted twice with ethyl acetate. The combined organiclayers were washed with brine, dried with anhydrous magnesium sulfate,filtered and concentrated. The residue was purified by flashchromatography (10:1 petroleum ether: ethyl acetate) to afford 18 g(51%) of the title compound.

Example 153d Methyl3-(2,6-dimethylphenoxy)-4-(2-(ethylcarbamoyl)-6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)benzoate

Example 153c (1.843 g, 4.82 mmol), Example 145g (1.5137 g, 4.38 mmol),sodium carbonate (1.627 g, 15.35 mmol),tris(dibenzylideneacetone)dipalladium(0) (0.201 g, 0.219 mmol), and1,3,5,7-tetramethyl-6-phenyl-2,4,6-trioxa-6-phosphaadamantane (0.218 g,0.745 mmol) were flow purged with nitrogen for 90 min. Degassedtetrahydrofuran (35.1 mL) and water (8.77 mL) were added. The reactionmixture was heated to 60° C. for 3 hours. The reaction mixture wascooled to ambient temperature and partitioned between ethyl acetate andwater. The organic layer was washed with brine, dried with anhydrousmagnesium sulfate, filtered and concentrated. The residue was purifiedby flash chromatography (10:1 petroleum ether:ethyl acetate) to afford2.0084 g (97%) of the title compound.

Example 153e3-(2,6-dimethylphenoxy)-4-(2-(ethylcarbamoyl)-6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)benzoicacid

To a solution of Example 153d (1.1175 g, 2.360 mmol) in tetrahydrofuran(17.70 mL) and water (5.90 mL) was added. lithium hydroxide monohydrate(0.990 g, 23.60 mmol). The reaction mixture was stirred at ambienttemperature over 2 nights. The reaction mixture was quenched with 1Nhydrochloric acid. The resulting suspension was filtered, and the solidwas rinsed with water and dried to afford 1.0213 g (94%) of the titlecompound.

Example 153f4-(2-(2,6-dimethylphenoxy)-4-((2-(methylamino)-2-oxoethyl)(pyridin-2-ylmethyl)carbamoyl)phenyl)-N-ethyl-6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-2-carboxamide

A solution of Example 153e and diisopropylethyl amine (0.13 M and 0.39 Min N,N-dimethylacetamide, respectively, 300 μL, 0.039 mmol Example 153e(1.0 equivalent) and 0.11 mmol diisopropylethyl amine (3.0equivalents)), O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate (0.16 M in N,N-dimethylacetamide, 300 μL, 0.048mmol, 1.2 equivalents), andN-methyl-2-((pyridin-2-ylmethyl)amino)acetamide (0.40 M inN,N-dimethylacetamide, 147 μL, 0.059 mmol, 1.5 equivalents) were stirreduntil complete. The reaction mixture was purified by reverse phasepreparative HPLC (C8, 5-100% acetonitrile in 0.1% trifluoroaceticacid/water) to afford 18.5 mg of the title compound (64%). ¹H NMR (400MHz, DMSO-d₆) δ 8.49 (s, 1H), 7.92 (s, 1H), 7.52 (d, J=7.7 Hz, 1H), 7.46(d, J=7.5 Hz, 2H), 7.32 (s, 1H), 7.20 (dd, J=7.6, 1.5 Hz, 1H), 7.05 (s,3H), 6.86 (s, 1H), 6.49 (s, 1H), 4.68 (s, 2H), 3.93-4.00 (m, 2H), 3.60(s, 3H), 3.31 (d, J=7.2 Hz, 2H), 2.60 (s, 3H), 1.93 (s, 6H), 1.14 (t,J=7.2 Hz, 3H). MS (APCI+) m/z 621.6 (M+H)⁺.

Example 1544-[2-(2,6-dimethylphenoxy)-4-{methyl[1-(propanoyloxy)piperidin-4-yl]carbamoyl}phenyl]-N-ethyl-6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-2-carboxamide

Example 154 was prepared according to the procedure used for thepreparation of Example 153f, substituting 4-(methylamino)piperidin-1-ylpropionate for N-methyl-2-((pyridin-2-ylmethyl)amino)acetamide. ¹H NMR(400 MHz, DMSO-d₆) δ 7.55 (d, J=7.7 Hz, 1H), 7.36 (s, 1H), 7.02-7.18 (m,4H), 6.90 (s, 1H), 6.31 (d, J=1.5 Hz, 1H), 4.05 (q, J=7.1 Hz, 4H), 3.61(s, 3H), 3.30 (q, J=7.2 Hz, 2H), 2.73 (s, 3H), 2.64 (t, J=12.9 Hz, 2H),2.03 (s, 6H), 1.56-1.69 (m, 2H), 1.47 (d, J=12.4 Hz, 2H), 1.17 (dt,J=18.0, 7.1 Hz, 6H). MS (APCI+) m/z 628.6 (M+H)⁺.

Example 1551-({4-[2-(2,4-difluorophenoxy)-5-(methylsulfonyl)phenyl]-6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-2-yl}methyl)-N,N-dimethyl-4-(2-oxopyrrolidin-1-yl)piperidine-4-carboxamideExample 155a 1-(2,4-difluorophenoxy)-4-(methylsulfonyl)-2-nitrobenzene

A mixture of 1-fluoro-4-(methylsulfonyl)-2-nitrobenzene (20 g, 91 mmol),2,4-difluorophenol (11.87 g, 91 mmol) and potassium carbonate (12.6 g,91 mmol) in DMSO (90 mL) was heated at 120° C. for 2 hours. The reactionmixture was quenched with water and extracted with ethyl acetate. Thecombined organic layers were washed with saturated aqueous sodiumchloride, dried over anhydrous magnesium sulfate, filtered, andconcentrated. The residue was purified by flash chromatography (silicagel, 1:1 ethyl acetate/hexanes) to provide the title compound (28 g, 89%yield).

Example 155b 2-(2,4-difluorophenoxy)-5-(methylsulfonyl)aniline

A solution of Example 155a (10.0 g, 30.4 mmol) in tetrahydrofuran (150mL) was added to 10% Pd/C (1.616 g, 15.18 mmol) in a 250 mL bottle andthe mixture was stirred for 24 hour under a 30 psi hydrogen atmosphereat 40° C. The mixture was filtered through a nylon membrane andconcentrated. The residue was purified flash chromatography (silica gel,70:30 ethyl acetate/hexanes) to provide the title compound (8.6 g, 55%yield).

Example 155c 1-(2,4-difluorophenoxy)-2-iodo-4-(methylsulfonyl)benzene

Example 155b (5.00 g, 16.7 mmol) in dioxane (30 mL) was treated withconcentrated HCl (150 mL) at 0° C. The reaction mixture was stirred at0° C. for 10 minutes. To this solution was added sodium nitrite (1.383g, 20.05 mmol) in water (6 mL). The reaction mixture was stirred at 0°C. for one hour. To this solution was added potassium iodide (5.55 g,33.4 mmol) in water (20 mL). The reaction mixture was stirred for twohours at 10° C. The reaction mixture was then partitioned between waterand ethyl acetate. The organic layer was extracted with additional ethylacetate twice. The combined organic layer was washed with saturatedaqueous sodium chloride, dried (anhydrous magnesium sulfate), filtered,and concentrated. The residue was purified by flash chromatography(silica gel, 2:3 ethyl acetate/hexanes) to provide the title compound(8.9 g, 89% yield)

Example 155d ethyl1-benzyl-4-(2-(2,4-difluorophenoxy)-5-(methylsulfonyl)phenyl)-6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-2-carboxylate

Example 16f (2.3 g, 5.27 mmol), Example 155c (2.270 g, 5.54 mmol),1,3,5,7-tetramethyl-6-phenyl-2,4,8-trioxa-6-phosphaadamantane (0.154 g,0.527 mmol), tris(dibenzylideneacetone)dipalladium(0) (0.121 g, 0.132mmol) and potassium phosphate (1.119 g, 5.27 mmol) were combined andsparged with argon for 30 minutes. A mixture of degassed dioxane (30 mL)and water (7.5 mL) was added and the reaction mixture was stirred at 60°C. for 16 hours. The reaction mixture was cooled to ambient temperatureand partitioned between ethyl acetate and water. The organic layer waswashed with saturated aqueous sodium chloride, dried (anhydrous sodiumsulfate), filtered, and concentrated. The residue was purified by flashchromatography (silica gel, 20-100% ethyl acetate in petroleum ether) toafford the title compound (1.77 g, 33.4% yield).

Example 155e ethyl4-(2-(2,4-difluorophenoxy)-5-(methylsulfonyl)phenyl)-6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-2-carboxylate

A mixture of Example 155d, anisole (1.585 mL, 14.51 mmol) andconcentrated sulfuric acid (4.3 mL, 81 mmol) in trifluoroacetic acid (20mL, 260 mmol) was heated at 90° C. for 4 hours. Excess trifluoroaceticacid was removed under reduced pressure, and the residue was partitionedbetween water (100 mL) and ethyl acetate (200 mL). The organic layer wasseparated, and the aqueous layer was extracted with additional ethylacetate (2×200 mL). The combined organic layers were washed withsaturated aqueous sodium bicarbonate (100 mL), followed by saturatedaqueous sodium chloride (100 mL), dried over anhydrous magnesiumsulfate, filtered, and concentrated. The crude material was taken intomethanol (50 mL) and the resulting solid was filtered, rinsed withmethanol, and dried to provide the title compound (3.1 g, 63% yield).

Example 155f4-[2-(2,4-difluorophenoxy)-5-(methylsulfonyl)phenyl]-2-(hydroxymethyl)-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one

To a suspension of Example 155e (0.20 g, 0.40 mmol) in tetrahydrofuran(5 mL) stirring at 0° C. was added lithium aluminum hydride (1M intetrahydrofuran, 0.398 mL, 0.398 mmol) and the mixture was stirred at 0°C. for two hours. The solvent was evaporated under reduced pressure andthe residue was partitioned between ethyl acetate (30 mL) and water (20mL). The mixture was filtered to remove the undissolved materials. Theaqueous layer was extracted with ethyl acetate (2×30 mL). The combinedorganic layers were dried over anhydrous sodium sulfate, filtered, andconcentrated. The residue was triturated with dichloromethane and theresulting solid was filtered and dried to provide the title compound(0.10 g, 55% yield).

Example 155g4-(2-(2,4-difluorophenoxy)-5-(methylsulfonyl)phenyl)-6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-2-carbaldehyde

To a solution of Example 155f (1.0 g, 2.2 mmol) in dichloromethane (50mL) at 0° C. was added Dess-Martin Periodinane (1.84 g, 4.34 mmol) andthe reaction mixture was stirred at 0° C. for 30 minutes. The reactionmixture was then stirred at ambient temperature for three hours. Asolution of sodium bisulfite (0.9 g, 9 mmol) in saturated aqueous sodiumbicarbonate (5 mL) was added, and the reaction mixture was stirred for15 minutes and extracted with ethyl acetate. The organic layer was dried(anhydrous sodium sulfate), filtered, and concentrated to provide thetitle compound (0.80 g, 70% yield).

Example 155h1-({4-[2-(2,4-difluorophenoxy)-5-(methylsulfonyl)phenyl]-6-methyl-7-oxo-6,7-dihydro-H-pyrrolo[2,3-c]pyridin-2-yl}methyl)-N,N-dimethyl-4-(2-oxopyrrolidin-1-yl)piperidine-4-carboxamide

Example 155h was prepared according to the procedure used for thepreparation of Example 16o, substituting Example 155g for Example 16nand N,N-dimethyl-4-(2-oxopyrrolidin-1-yl)piperidine-4-carboxamide for1-(pyridin-4-yl)piperazine. The reaction mixture was concentrated andthe crude material was purified by reverse phase Prep HPLC (C18, 10-50%acetonitrile in 0.1% trifluoroacetic acid/water) to provide thetrifluoroacetic acid salt of the title compound. ¹H NMR (400 MHz,Pyridine-d₅) δ 13.59 (d, J=2.3 Hz, 1H), 8.47 (d, J=2.4 Hz, 1H), 8.22(dd, J=8.7, 2.4 Hz, 1H), 7.41 (td, J=9.1, 5.5 Hz, 1H), 7.31-7.23 (m,2H), 7.15 (dd, J=8.6, 1.1 Hz, 1H), 7.04 (dddd, J=11.8, 7.3, 3.6, 2.1 Hz,1H), 6.66 (d, J=1.9 Hz, 1H), 4.01 (s, 2H), 3.63 (s, 3H), 3.42 (s, 3H),3.34 (t, J=6.9 Hz, 2H), 3.09-2.93 (m, 4H), 2.89 (s, 6H), 2.48 (d, J=14.8Hz, 2H), 2.27 (t, J=8.1 Hz, 2H), 2.14 (dt, J=14.1, 7.7 Hz, 2H), 1.78 (p,J=7.5 Hz, 2H). MS (APCI+) m/z 681.9 (M+H)⁺.

Example 1564-[2-(2,4-difluorophenoxy)-5-(methylsulfonyl)phenyl]-6-methyl-2-{[3-(1H-1,2,4-triazol-1-yl)azetidin-1-yl]methyl}-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one

Example 156 was prepared according to the procedure used for thepreparation of Example 16o, substituting Example 155g for Example 16nand 1-(azetidin-3-yl)-1H-1,2,4-triazole for 1-(pyridin-4-yl)piperazine.The reaction mixture was concentrated and the crude material waspurified by reverse phase Prep HPLC (C18, 10-50% acetonitrile in 0.1%trifluoroacetic acid/water) to provide the trifluoroacetic acid salt ofthe title compound. ¹H NMR (400 MHz, Pyridine-d₅) δ 13.76 (s, 1H), 8.95(s, 1H), 8.47 (d, J=2.4 Hz, 1H), 3.85-3.68 (m, 3H), 8.34 (s, 1H), 8.21(dd, J=8.7, 2.5 Hz, 1H), 7.45-7.29 (m, 2H), 7.14 (d, J=8.7 Hz, 1H),7.06-6.95 (m, 2H), 6.59 (d, J=2.0 Hz, 1H), 3.99 (s, 2H), 3.80 (t, J=7.4Hz, 2H), 3.73 (dd, J=7.9, 6.2 Hz, 2H), 3.63 (s, 3H), 3.42 (s, 4H), 2.50(m, 1H). MS (APCI+) m/z 566.8 (M+H)⁺.

Example 157N-ethyl-4-[5-(ethylsulfonyl)-2-{2-methyl-6-[(2-oxoazetidin-1-yl)methyl]phenoxy}phenyl]-6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-2-carboxamideExample 157a1-(2-(2-bromo-4-(ethylsulfonyl)phenoxy)-3-methylbenzyl)azetidin-2-one

A mixture of Example 145c (300 mg, 0.669 mmol), azetidin-2-one (71.4 mg,1.004 mmol), potassium carbonate (463 mg, 3.35 mmol), andtetrabutylammonium bromide (21.6 mg, 0.067 mmol) in acetonitrile (10 mL)was heated at 90° C. for two days. The mixture was cooled to ambienttemperature and partitioned with ethyl acetate and water. The organicphase was separated, dried over anhydrous sodium sulfate, filtered, andevaporated under reduced pressure. The residue was purified by flashchromatography (silica gel, 0-100% ethyl acetate/petroleum ethergradient), to provide the title compound (0.070 g, 24% yield).

Example 157bN-ethyl-4-[5-(ethylsulfonyl)-2-{2-methyl-6-[(2-oxoazetidin-1-yl)methyl]phenoxy}phenyl]-6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-2-carboxamide

Example 157b was prepared according to the procedure described for thepreparation of Example 145h, substituting Example 157a for Example 145d.¹H NMR (400 MHz, CD₃OD) δ 8.31 (d, J=2.3 Hz, 1H), 8.13 (dd, J=8.7, 2.3Hz, 1H), 7.88 (s, 1H), 7.57 (m, 3H), 7.29 (s, 1H), 6.97 (d, J=8.7 Hz,1H), 4.84 (m, 1H), 4.35 (m, 1H), 4.04 (s, 3H), 3.71 (q, J=7.3 Hz, 3H),3.56 (q, J=7.4 Hz, 1H), 3.27 (t, J=3.9 Hz, 2H), 2.96 (m, 2H), 2.34 (s,3H), 1.57 (t, J=7.4 Hz, 3H), 1.52 (t, J=7.3 Hz, 3H). MS (ESI+) m/z(M+H)⁺.

Example 158 N-ethyl-4-[5-(ethylsulfonyl)-2-{2-methyl-6-[(2-oxopyridin-1(2H)-yl)methyl]phenoxy}phenyl]-6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-2-carboxamideExample 158a1-(2-(2-bromo-4-(ethylsulfonyl)phenoxy)-3-methylbenzyl)pyridin-2(1H)-one

Example 158a was prepared according to the procedure described for thepreparation of Example 151a, substituting pyridin-2(1H)-one forpyrrolidin-2-one. The crude mixture was purified by flash columnchromatography on silica gel, eluting with 20-100% methanol indichloromethane to provide the title compound.

Example 158b N-ethyl-4-[5-(ethylsulfonyl)-2-{2-methyl-6-[(2-oxopyridin-1(2H)-yl)methyl]phenoxy}phenyl]-6-methyl-7-oxo-6,7-dihydro-H-pyrrolo[2,3-c]pyridine-2-carboxamide

Example 158b was prepared according to the procedure described for thepreparation of Example 145h, substituting Example 158a for Example 145d.¹H NMR (300 MHz, CDCl₃) δ 10.92 (s, 1H), 7.94 (d, J=2.2 Hz, 1H), 7.77(m, 1H), 7.63 (dd, J=8.6, 2.3 Hz, 1H), 7.22 (m, 3H), 7.12 (d, J=7.0 Hz,1H), 7.01 (s, 1H), 6.44 (dd, J=8.8, 5.5 Hz, 2H), 6.07 (t, J=6.6 Hz, 1H),5.55 (d, J=14.5 Hz, 1H), 4.63 (d, J=14.6 Hz, 1H), 3.74 (s, 3H), 3.50 (m,2H), 3.13 (q, J=7.3 Hz, 2H), 1.96 (s, 3H), 1.30 (t, J=7.4 Hz, 3H), 1.24(t, J=7.2 Hz, 2H). MS (ESI+) m/z (M+H)⁺.

Example 1593-[({4-[2-(2,4-difluorophenoxy)-5-(methylsulfonyl)phenyl]-6-methyl-7-oxo-6,7-dihydro-H-pyrrolo[2,3-c]pyridin-2-yl}methyl)amino]propanamide

Example 159 was prepared according to the procedure used for thepreparation of Example 16o, substituting Example 155g for Example 16nand 3-aminopropanamide for 1-(pyridin-4-yl)piperazine. ¹H NMR (400 MHz,DMSO-d₆) δ 11.85 (s, 1H), 7.98 (d, J=2.3 Hz, 1H), 7.87 (dd, J=8.7, 2.4Hz, 1H), 7.56-7.46 (m, 1H), 7.46-7.37 (m, 2H), 7.33 (s, 1H), 7.21-7.12(m, 1H), 6.98 (d, J=8.6 Hz, 1H), 6.73 (s, 1H), 6.16 (s, 1H), 3.73 (s,2H), 3.58 (s, 3H), 3.26 (s, 3H), 2.60 (t, 2H), 2.17 (t, J=6.7 Hz, 2H).MS (APCI+) m/z 531.2 (M+H)⁺.

Example 160 methyl3-[{3-(2,6-dimethylphenoxy)-4-[2-(ethylcarbamoyl)-6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl]benzoyl}(phenyl)amino]propanoate

A solution of Example 153e (0.11 M in pyridine, 200 μL, 0.022 mmoL),1-ethyl-3-[3-(dimethylamino)propyl]-carbodiimide hydrochloride (6.42 mg0.041 mmol, 1.0 equivalent), and methyl 3-(phenylamino)propanoate (0.40M in N,N-dimethylacetamide, 76.2 μL, 0.030 mmol, 1.4 equivalents) werecombined and stirred overnight at 40° C. The reaction mixture waspurified by reverse phase preparative HPLC (C8, 5-100% acetonitrile in0.1% trifluoroacetic acid/water) to afford 10.9 mg of the title compound(81%). ¹H NMR (400 MHz, DMSO-d₆) δ 7.36 (d, J=7.8 Hz, 1H), 7.17-7.25 (m,4H), 7.14 (dd, J=7.8, 1.7 Hz, 1H), 7.07 (s, 3H), 6.86-6.97 (m, 2H), 6.76(s, 1H), 6.16 (d, J=1.7 Hz, 1H), 3.98 (t, J=7.0 Hz, 2H), 3.56 (s, 3H),3.50 (s, 3H), 3.29 (q, J=7.2 Hz, 2H), 2.50-2.57 (m, 2H), 1.79 (s, 6H),1.14 (t, J=7.2 Hz, 3H). MS (APCI+) m/z 621.2 (M+H)⁺.

Example 1614-[4-{benzyl[3-(morpholin-4-yl)propyl]carbamoyl}-2-(2,6-dimethylphenoxy)phenyl]-N-ethyl-6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-2-carboxamide

Example 161 was prepared according to the procedure used for thepreparation of Example 160, substitutingN-benzyl-3-morpholinopropan-1-amine for methyl3-(phenylamino)propanoate. ¹H NMR (400 MHz, DMSO-d₆) δ 7.55 (d, J=7.8Hz, 1H), 7.28-7.34 (m, 4H), 7.19 (dd, J=7.8, 1.6 Hz, 1H), 7.04-7.11 (m,4H), 6.85 (s, 1H), 6.38 (d, J=1.5 Hz, 1H), 4.52 (s, 2H), 3.81 (s, 4H),3.60 (s, 3H), 3.31-3.38 (m, 2H), 3.26-3.32 (m, 2H), 3.17 (s, 4H),2.99-3.08 (m, 2H), 1.87-1.97 (m, 8H), 1.14 (t, J=7.2 Hz, 3H). MS (APCI+)m/z 676.3 (M+H)⁺.

Example 162 4-[4-{(3,4-dichlorophenyl)[2-(thiomorpholin-4-yl)ethyl]carbamoyl}-2-(2,6-dimethylphenoxy)phenyl]-N-ethyl-6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-2-carboxamideExample 162a3-(2,6-dimethylphenoxy)-4-(2-(ethylcarbamoyl)-6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)benzoylchloride

Example 153e (30 mg, 0.065 mmol) was suspended in dichloromethane (1mL). Oxalyl chloride (12 μL, 0.13 mmol, 2 equivalents) was added,followed by a drop of N,N-dimethylformamide. The reaction mixture wasstirred at ambient temperature until complete consumption of Example153e. The reaction mixture was dried under a stream of nitrogen,dissolved in dichloromethane (2 mL) and dried again under nitrogen.

Example 162b4-(4-((3,4-dichlorophenyl)(2-thiomorpholinoethyl)carbamoyl)-2-(2,6-dimethylphenoxy)phenyl)-N-ethyl-6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-2-carboxamide

To Example 162a (10 mg, 0.021 mmol) in tetrahydrofuran (300 uL) wasadded 3,4-dichloro-N-(2-thiomorpholinoethyl)aniline (0.40 M inN,N-dimethylacetamide, 163 μL, 0.065 mmol, 3.0 equivalents) and thereaction mixture was allowed to stir overnight at ambient temperature.The reaction mixture was purified by reverse phase preparative HPLC (C8,5-100% acetonitrile in 0.1% trifluoroacetic acid/water) to afford 8.9 mgof the title compound (48%). ¹H NMR (400 MHz, DMSO-d₆) δ 7.48 (d, J=7.8Hz, 1H), 7.41 (d, J=8.6 Hz, 1H), 7.24-7.35 (m, 3H), 7.07 (s, 3H), 6.99(dd, J=8.6, 2.6 Hz, 1H), 6.77 (s, 1H), 6.11 (s, 1H), 4.06 (t, J=7.0 Hz,2H), 3.58 (s, 3H), 3.26-3.35 (m, 4H), 3.14 (t, J=7.0 Hz, 2H), 2.84 (t,J=5.2 Hz, 4H), 1.81 (s, 6H), 1.14 (t, J=7.2 Hz, 3H). MS (APCI+) m/z732.6 (M+H)⁺.

Example 163N-{4-(2,4-difluorophenoxy)-3-[2-(3-methoxyprop-1-yn-1-yl)-6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl]phenyl}ethanesulfonamideExample 163a 2-bromo-1-(2,4-difluorophenoxy)-4-nitrobenzene

2-Bromo-1-fluoro-4-nitrobenzene (15 g, 68.2 mmol), 2,4-difluorophenol(7.82 mL, 82 mmol), and cesium carbonate (26.7 g, 82 mmol) were combinedin DMSO (75 mL) then heated to 110° C. for 1 hour. After cooling, thereaction mixture was partitioned between water and ethyl acetate. Theaqueous layer was extracted with additional ethyl acetate twice. Thecombined organic layers were washed with saturated aqueous sodiumchloride, dried over anhydrous magnesium sulfate, filtered, andconcentrated to give the title compound (22.51 g, 68.2 mmol, 100%).

Example 163b 3-bromo-4-(2,4-difluorophenoxy)aniline

A mixture of Example 66a (42 g, 127 mmol), iron (35.5 g, 636 mmol), andammonium chloride (13.61 g, 254 mmol) in tetrahydrofuran (234 mL),ethanol (234 mL), and water (78 mL) was heated under reflux at 100° C.for 2 hours. The mixture was cooled to just below reflux and filteredthrough Celite. The filter cake was washed with warm methanol. Theresulting combined filtrate solution was concentrated under reducedpressure to remove organics, and then neutralized to a pH of about 8with saturated NaHCO₃. The resulting aqueous solution was extracted withethyl acetate three times. The combined organics were washed withsaturated aqueous sodium chloride, dried over anhydrous magnesiumsulfate, filtered, concentrated to provide the title compound (38 g, 127mmol, 100% yield).

Example 163c4-(2,4-difluorophenoxy)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline

Example 163b (15.04 g, 50.1 mmol),4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (25.5 g, 100mmol), potassium acetate (10.82 g, 110 mmol),1,3,5,7-tetramethyl-6-phenyl-2,4,8-trioxa-6-phosphaadamantane (1.465 g,5.01 mmol), and tris(dibenzylideneacetone)dipalladium(0) (1.377 g, 1.504mmol) were degassed under argon for 30 minutes. Dioxane (200 mL),degassed with argon for 30 minutes, was then cannulated and the mixtureheated at 80° C. for 22 hours. The cooled mixture was filtered throughCelite, rinsed with ethyl acetate (100 mL), washed with brine (150 mL)and water (150 mL), and partitioned. The aqueous was extracted withethyl acetate (3×150 mL). The combined organics were washed with brine,dried (anhydrous MgSO₄), filtered, and concentrated to an amber oil.Purification by flash chromatography (ethyl acetate/Hexanes, 0:25%gradient) afforded the title compound (12.4 g, 71% yield).

Example 163d 4-bromo-2-iodo-7-methoxy-1-tosyl-1H-pyrrolo[2,3-c]pyridine

In a 1 L round-bottomed flask charged with tetrahydrofuran (200 ml)cooled to −78° C. was added butyllithium (36.7 ml, 92 mmol) followed bydiisopropylamine (9.29 g, 92 mmol) added dropwise. The resulting mixturewas stirred at −78° C. for 45 minutes. To a mixture of Example 1c (25 g,65.6 mmol) in tetrahydrofuran (200 ml) stirred at −78° C. was addeddropwise the lithium diisopropylamide solution generated as describedabove. The mixture was stirred at −78° C. for 1.5 hours. To theresulting mixture stirred at −78° C. was added dropwise the solution ofdiiodine (38.3 g, 151 mmol) in tetrahydrofuran (100 mL) and the mixturestirred at −78° C. for 2 hours. The reaction mixture was quenched withNa₂S₂O₃ solution, extracted with ethyl acetate (2×1000 mL) followed bydichloromethane (4×1000 mL), and the organic phase was dried overanhydrous sodium sulfate, filtered, and concentrated in vacuo. Theresidue was triturated with dichloromethane. The solid was collected anddried in vacuo to give the title compound (19.95 g, 39.3 mmol, 60%yield).

Example 163e 4-bromo-2-iodo-1-tosyl-1H-pyrrolo[2,3-c]pyridin-7(6H)-one

To a mixture of Example 163d (14 g, 27.6 mmol) in acetonitrile (260 mL)was added sodium iodide (6.62 g, 44.2 mmol) followed bychlorotrimethylsilane (4.80 g, 44.2 mmol) added dropwise. The resultingmixture was stirred at room temperature for 30 minutes and then water(0.249 g, 13.80 mmol) was added. The resulting mixture was stirred at65° C. for 3 hours, cooled to ambient temperature, and filtered. Theresulting solid was collected, suspended in dichloromethane, andfiltered. The eluent was dried over anhydrous sodium sulfate andconcentrated in vacuo to give the desired product. The filtrate wasconcentrated in vacuo, purified by column chromatography (silica gel,dichloromethane/methanol, 20:1) to give additional desired product. Thecombined yield as 12 g (88% yield).

Example 163f4-bromo-2-iodo-6-methyl-1-tosyl-1H-pyrrolo[2,3-c]pyridin-7(6H)-one

To a solution of Example 163e (11 g, 22.31 mmol) in DMF (130 ml) wasadded sodium hydride (1.160 g, 29.0 mmol) in portions at 0° C., and themixture was stirred for 30 minutes. Then iodomethane (4.12 g, 29.0 mmol)was added dropwise to the above mixture. The resulting mixture wasstirred at room temperature for 3 hours. The reaction mixture wasquenched with aqueous ammonium chloride solution. The resultingsuspension was filtered and the filter cake was dissolved indichloromethane, dried over anhydrous sodium sulfate, filtered andconcentrated under reduced pressure. The residue was dissolved indichloromethane, and methanol was added. The suspension was filtered andthe filter cake was dried to the title compound (5.0 g, 44% yield).

Example 163g4-bromo-2-(3-methoxyprop-1-yn-1-yl)-6-methyl-1-tosyl-1H-pyrrolo[2,3-c]pyridin-7(6H)-one

A mixture of Example 163f (51 mg, 0.101 mmol), 3-methoxyprop-1-yne (10.6mg, 0.151 mmol), copper(I) iodide (3.83 mg, 0.020 mmol),bis(triphenylphosphine)palladium(II) chloride (7.1 mg), andtriethylamine (204 mg, 2.01 mmol) in dimethylformamide (2 mL) wasdegassed and heated at 80° C. under argon for 3 hours. The mixture wascooled to ambient temperature and combined with the contents of anidentical reaction mixture. The mixture was partitioned between ethylacetate and ammonium chloride solution, and the organic layer separated,dried over anhydrous magnesium sulfate, filtered, and concentrated underreduced pressure. The residue was purified by flash chromatography(silica gel, 0-2% methanol/dichloromethane gradient) and followed bytrituration with diethyl ether to afford the title compound (55.7 mg,61% yield from combined reactions).

Example 163h4-(5-amino-2-(2,4-difluorophenoxy)phenyl)-2-(3-methoxyprop-1-yn-1-yl)-6-methyl-1-tosyl-1H-pyrrolo[2,3-c]pyridin-7(6H)-one

A mixture of Example 163g (55.6 mg, 0.124 mmol), Example 163c (86 mg,0.247 mmol), cesium fluoride (56.4 mg, 0.371 mmol), andtetrakis(triphenylphosphine)palladium(0) (14.3 mg, 0.012 mmol) wassparged under argon for 15 minutes. To this mixture was added degassed1,2-dimethoxyethane (5 mL) and degassed methanol (2.5 mL), and themixture was heated at 100° C. for 50 minutes. The reaction mixture wascooled to ambient temperature, and partitioned between ethyl acetate andsaturated aqueous ammonium chloride. The organic layer was dried overanhydrous magnesium sulfate, filtered, and evaporated under reducedpressure. The residue was purified by flash chromatography (silica gel,3:2 ethyl acetate/heptane) to provide the title compound (18 mg).

Example 163iN-{4-(2,4-difluorophenoxy)-3-[2-(3-methoxyprop-1-yn-1-yl)-6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl]phenyl}ethanesulfonamide

To Example 163h (18 mg, 0.031 mmol) in dichloromethane (8 mL) at 0° C.was added triethylamine (0.017 ml, 0.122 mmol) followed by the dropwiseaddition of ethanesulfonyl chloride (8.68 μL, 0.092 mmol). The reactionmixture was stirred at ambient temperature for 1 hour, and additionalethanesulfonyl chloride (20 μL, 0.21 mmol) was added twice. The reactionmixture was heated at 45° C. for 2 hours and then at ambient temperaturefor 18 hours. The mixture was partitioned between dichloromethane andsaturated aqueous ammonium chloride and the organic layer dried overanhydrous magnesium sulfate, filtered, and concentrated under reducedpressure. The residue was dissolved in dioxane (2.5 mL) and 5N aqueoussodium hydroxide (1 mL) and the mixture heated at 90° C. for 1.5 hours.The mixture was cooled to ambient temperature, and partitioned betweenethyl acetate and saturated aqueous sodium chloride. The pH was adjustedto pH=2 by the addition of 1 N HCl, and the mixture further extractedwith ethyl acetate. The combined organic layers were dried overanhydrous magnesium sulfate, filtered, and evaporated. The residue wastriturated with ethyl acetate/hexane to provide the title compound (6mg, 37% yield). ¹H NMR (400 MHz, DMSO-d₆) δ 12.65 (s, 1H), 9.78 (s, 1H),7.37 (m, 3H), 7.20 (dd, J=8.8, 2.7 Hz, 1H), 7.08 (td, J=9.1, 5.6 Hz,1H), 6.99 (m, 1H), 6.92 (d, J=8.8 Hz, 1H), 6.46 (s, 1H), 4.33 (s, 2H),3.52 (s, 3H), 3.11 (q, J=7.3 Hz, 3H), 1.23 (m, 3H). ). MS (APCI+) m/z528.3 (M+H)⁺.

Biological Examples Bromodomain Domain Binding Assay

A time-resolved fluorescence resonance energy transfer (TR-FRET) assaywas used to determine the affinities of compounds of the Examples listedin Table 1 for each bromodomain of BRD4. His-tagged first (BD1: aminoacids K57-E168) and second (BD2: amino acids E352-E168) bromodomains ofBRD4 were expressed and purified. An Alexa647-labeled BET-inhibitor wasused as the fluorescent probe in the assay.

Synthesis of Alexa647-Labeled Bromodomain Inhibitor Compound:2-((6S,Z)-4-(4-chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl)aceticacid

Methyl2-((6S,Z)-4-(4-chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl)acetate(see e.g., WO 2006129623)(100.95 mg, 0.243 mmol was suspended in 1 mLmethanol to which was added a freshly prepared solution of lithiumhydroxide monohydrate (0.973 mL, 0.5 M, 0.487 mmol) and shaken atambient temperature for 3 hours. The methanol was evaporated and the pHadjusted with aqueous hydrochloric acid (1 M, 0.5 mL, 0.5 mmol) andextracted four times with ethyl acetate. The combined ethyl acetatelayers were dried over magnesium sulfate and evaporated to afford2-((6S,Z)-4-(4-chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl)aceticacid (85.3 mg, 87.0%); ESI-MS m/z=401.1 [(M+H)⁺] which was used directlyin the next reaction.

N-(2-(2-(2-aminoethoxy)ethoxy)ethyl)-2-((6S,Z)-4-(4-chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl)acetamidebis(2,2,2-trifluoroacetate)

2-((6S,Z)-4-(4-chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl)aceticacid) (85.3 mg, 0.213 mmol) was combined with2,2′-(ethane-1,2-diylbis(oxy))diethanamine (Sigma-Aldrich, 0.315 mg,2.13 mmol) were combined in 5 mL anhydrous dimethylformamide.(1H-benzo[d][1,2,3]triazol-1-yloxy)tripyrrolidin-1-ylphosphoniumhexafluorophosphate(V) (PyBOB, CSBio, Menlo Park Calif.; 332 mg, 0.638mmol) was added and the reaction shaken at ambient temperature for 16hours. The reaction was diluted to 6 mL with dimethylsulfoxide:water(9:1, v:v) and purified in two injections with time collection WatersDeltapak C18 200×25 mm column eluted with a gradient of 0.1%trifluoroacetic acid (v/v) in water and acetonitrile. The fractionscontaining the two purified products were lyophilized to affordN-(2-(2-(2-aminoethoxy)ethoxy)ethyl)-2-((6S,Z)-4-(4-chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl)acetamidebis(2,2,2-trifluoroacetate) (134.4 mg, 82.3%); ESI-MS m/z=531.1[(M+H)+]; 529.1 [(M−H)⁻] and(S,Z)—N,N′-(2,2′-(ethane-1,2-diylbis(oxy))bis(ethane-2,1-diyl))bis(2-((6S,Z)-4-(4-chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl)acetamide)bis(2,2,2-trifluoroacetate) (3.0 mg, 1.5%); ESI-MS m/z=913.2 [(M+H)+];911.0 [(M−H)⁻].

N-(2-(2-(2-amido-(Alexa647)-ethoxy)ethoxy)ethyl)-2-((6S,Z)-4-(4-chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl)acetamide(2,2,2-trifluoroacetate)

N-(2-(2-(2-aminoethoxy)ethoxy)ethyl)-2-((6S,Z)-4-(4-chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl)acetamidebis(2,2,2-trifluoroacetate) (5.4 mg, 0.0071 mmol) was combined withAlexa Fluor® 647 carboxylic Acid, succinimidyl ester (Life Technologies,Grand Island, N.Y.; 3 mg, 0.0024 mmol) were combined in 1 mL anhydrousdimethylsulfoxide containing diisopropylethylamine (1% v/v) and shakenat ambient temperature for 16 hours. The reaction was diluted to 3 mLwith dimethylsulfoxide:water (9:1, v:v) and purified in one injectionwith time collection Waters Deltapak C18 200×25 mm column eluted with agradient of 0.1% trifluoroacetic acid (v/v) in water and acetonitrile.The fractions containing the purified product were lyophilized to affordN-(2-(2-(2-amido-(Alexa647)-ethoxy)ethoxy)ethyl)-2-((6S,Z)-4-(4-chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl)acetamide(2,2,2-trifluoroacetate)(1.8 mg); MALDI-MS m/z=1371.1, 1373.1 [(M+H)⁺] as a dark blue powder.

Assay

Compound dilution series were prepared in DMSO via a 3-fold serialdilution from 2.5 mM to 42 nM. Compounds were then diluted 6:100 inassay buffer (20 mM Sodium Phosphate, pH 6.0, 50 mM NaCl, 1 mMEthylenediaminetetraacetic acid disodium salt dihydrate, 0.01% TritonX-100, 1 mM DL-Dithiothreitol) to yield 3× working solutions. Sixmicroliters (μL) of the working solution was then transferred to white,low-volume assay plates (Costar #3673). A 1.5× assay mixture containingHis-tagged bromodomain, Europium-conjugated anti-His antibody(Invitrogen PV5596) and the Alexa-647-conjugated probe molecule was alsoprepared. Twelve μL of this solution were added to the assay plate toreach a final volume of 18 μL. The final concentration of 1× assaybuffer contains 2% DMSO, 50 μM-0.85 nM compound, 8 nM His-taggedbromodomain, 1 nM Europium-conjugated anti-His-tag antibody and 100 nMor 30 nM probe (for BDI or BDII, respectively). After a one-hourincubation at room temperature, TR-FRET ratios were determined using anEnvision multilabel plate reader (Ex 340, Em 495/520).

TR-FRET data were normalized to the means of 24 no-compound controls(“high”) and 8 controls containing 1 μM un-labeled probe (“low”).Percent inhibition was plotted as a function of compound concentrationand the data were fit with the 4 parameter logistic equation to obtainIC₅₀s. Inhibition constants (K_(i)) were calculated from the IC₅₀s,probe K_(d) and probe concentration. Typical Z′ values were between 0.65and 0.75. The minimum significant ratio was determined to evaluate assayreproducibility (Eastwood et al., (2006) J Biomol Screen, 11: 253-261).The MSR was determined to be 2.03 for BDI and 1.93 for BDII, and amoving MSR (last six run MSR overtime) for both BDI and BDII wastypically <3. The K_(i) values are reported in Table 1.

MX-1 Cell Line Proliferation Assay

The impact of compounds of the Examples on cancer cell proliferation wasdetermined using the breast cancer cell line MX-1 (ATCC) in a 3-dayproliferation assay and the data are reported in Table 1.

Method A:

MX-1 cells were maintained in RPMI 1640 medium (Sigma) supplemented with10% FBS at 37 C° and an atmosphere of 5% CO₂. For compound testing, MX-1cells were plated in 96-well black bottom plates at a density of 5000cells/well in 90 μL of culture media and incubated at 370 overnight toallow cell adhesion and spreading. Compound dilution series wereprepared in DMSO via a 3-fold serial dilution from 3 mM to 0.1 μM. TheDMSO dilution series were then diluted 1:100 in phosphate bufferedsaline, and 10 μL of the resulted solution were added to the appropriatewells of the MX-1 cell plate. The final compound concentrations in thewells were 3, 1, 0.3, 0.1, 0.03, 0.01, 0.003, 0.001, 0.0003 and 0.0001μM. After the addition of compounds, the cells were incubated for 72more hours and the amounts of viable cells were determined using theCell Titer Glo assay kit (Promega) according to manufacturer suggestedprotocol.

Luminescence readings from the Cell Titer Glo assay were normalized tothe DMSO treated cells and analyzed using the GraphPad Prism softwarewith sigmoidal curve fitting to obtain EC₅₀s. The minimum significantratio (MSR) was determined to evaluate assay reproducibility (Eastwoodet al., (2006) J Biomol Screen, 11: 253-261). The overall MSR wasdetermined to be 2.1 and a moving MSR (last six run MSR overtime) hasbeen <2.

Method B:

MX-1 cells were maintained in RPMI 1640 medium (Sigma) supplemented with10% FBS at 37 C° and an atmosphere of 5% CO₂. For compound testing, MX-1cells were plated in 384-well white with clear, flat bottom plates at adensity of 750 cells/well in 25 μL of culture media and incubated at 370overnight to allow cell adhesion and spreading. Ten point compounddilution series were prepared in DMSO via a 3-fold serial dilution fromeither 10 μM or 1 μM stock and added directly to the appropriate wellsof the MX-1 cell plate by an ECHO liquid handler (Labcyte). The finalcompound concentrations in the wells were 10, 3.25, 1, 0.25, 0.124,0.040, 0.0124, 0.0031, 0.0015 and 0.0005 μM or 1, 0.33, 0.1, 0.025,0.0124, 0.004, 0.0012, 0.0003, 0.00015, 0.00005 μM, depending on theconcentration of the compound stock solution. After the addition ofcompounds, the cells were incubated for 72 more hours and the amounts ofviable cells were determined using the Cell Titer Glo assay kit(Promega) according to manufacturer suggested protocol.

Luminescence readings from the Cell Titer Glo assay were normalized tothe DMSO treated cells and analyzed using Accelrys Assay Explorer 3.3software with sigmoidal curve fitting to obtain EC₅₀s. The minimumsignificant ratio (MSR) was determined to evaluate assay reproducibility(Eastwood et al., (2006) J Biomol Screen, 11: 253-261). The overall MSRwas determined to be 3.3 and a moving MSR (last six run MSR overtime)has averaged 2.1.

TABLE 1 TR-FRET TR-FRET Binding Ki: Binding Ki: Cellular BRD4 BRD4proliferation: EC₅₀ Exam- (BDI_K57-E168) (BDII_E352-M457) (μM) ple #(μM) (μM) Method A Method B 1 0.026 0.055 0.151 ND 2 0.057 0.0040 0.110ND 3 0.088 0.0028  0.0368 ND 4 0.011 0.0017  0.0163 ND 5 0.016 0.0017 0.0401 ND 6 0.014 0.0020  0.0291 ND 7 0.032 0.0069 0.139 ND 8 0.00150.0018  0.0449 ND 9 0.0017 0.0020  0.0653 ND 10 0.072 0.0083  0.0982 ND11 0.0008 0.0010 0.452 ND 12 0.0018 0.0016  0.0684 ND 13 0.042 0.00740.307 ND 14 0.071 0.014 0.184 ND 15 0.0046 0.0026 0.105 ND 16 0.00250.030 0.202 ND 17 0.0044 0.060 ND ND 18 0.0044 0.048 ND ND 19 0.00610.062 ND ND 20 0.0049 0.048 0.101 ND 21 0.033 0.010 0.487 ND 22 0.0180.015 >1    ND 23 0.011 0.0087 >1    ND 24 0.015 0.012 >1    ND 25 0.0190.0061 0.134 ND 26 0.027 0.015 ND ND 27 0.026 0.011 0.442 ND 28 0.0130.011 0.195 ND 29 0.019 0.0091 >1    ND 30 0.028 0.017 >1    ND 31 0.0210.011 0.443 ND 32 0.021 0.010 ND ND 33 0.0081 0.0031 >1    ND 34 0.0150.0036 0.155 ND 35 0.0031 0.0019 0.406 ND 36 0.014 0.0057 0.255 ND 370.018 0.0060 ND ND 38 0.0051 0.0019 0.103 ND 39 0.0046 0.0021  0.0974 ND40 0.0054 0.0020 0.143 ND 41 0.011 0.0051 ND ND 42 0.0091 0.0035 0.157ND 43 0.0050 0.0030 0.451 ND 44 0.0049 0.0021 0.391 ND 45 0.016 0.0033ND ND 46 0.010 0.0018  0.0431 ND 47 0.0059 0.0027 ND ND 48 0.0078 0.00240.172 ND 49 0.0044 0.0010  0.0738 ND 50 0.0034 0.0012  0.0405 ND 510.0050 0.0030 >1    ND 52 0.0020 0.0011  0.0386 ND 53 0.0034 0.00100.144 ND 54 0.0032 0.0011 >1    ND 55 0.0069 0.0028 0.393 ND 56 0.00880.0034 ND ND 57 0.0053 0.0022 >1    ND 58 0.0047 0.0024 0.152 ND 59 NDND ND ND 60 0.0079 0.0020  0.0641 ND 61 0.0037 0.0013  0.0430 ND 620.0031 0.0014  0.0511 ND 63 0.0013 0.0033  0.0094 ND 64 0.0052 0.0034 0.0526 ND 65 0.0069 0.0021  0.0400 ND 66 0.0038 0.0017  0.0547 ND 670.0043 0.0028  0.0506 ND 68 0.010 0.0047 ND ND 69 0.0041 0.0016  0.0933ND 70 0.016 0.0065 ND ND 71 0.033 0.019 ND ND 72 0.0074 0.0041 ND ND 730.0056 0.0035  0.0624 ND 74 0.0043 0.0014  0.0451 ND 75 0.0085 0.00290.112 ND 76 0.0033 0.0011  0.0499 ND 77 0.011 0.0028  0.0692 ND 780.0009 0.0006  0.0140 ND 79 0.0078 0.0027 ND ND 80 0.019 0.0046 0.128 ND81 0.035 0.010 ND ND 82 0.039 0.0085 0.221 ND 83 0.0053 0.0035  0.0899ND 84 0.0047 0.0089  0.0878 ND 85 0.008 0.060 >1    ND 86 0.024 0.075 NDND 87 0.021 0.034 0.325 ND 88 0.0049 0.023 ND ND 89 0.022 0.044 ND ND 900.014 0.025 ND ND 91 0.0050 0.0075 ND ND 92 0.015 0.033 ND ND 93 0.0190.024 ND ND 94 0.030 0.020 ND ND 95 0.022 0.016 ND ND 96 0.0170.021 >1    ND 97 0.010 0.028 ND ND 98 0.014 0.020 ND ND 99 0.012 0.028ND ND 100 ND ND ND ND 101 0.0060 0.0058  0.0729 ND 102 0.0060 0.0068 0.0673 ND 103 0.0041 0.0049 ND ND 104 0.0046 0.0040 0.176 ND 105 0.00720.017 ND ND 106 0.0079 0.0065 ND ND 107 0.0030 0.0089  0.0235 ND 1080.0034 0.0056 0.299 ND 109 0.0016 0.0083  0.0181 ND 110 0.0011 0.0022 0.0104 ND 111 0.0046 0.012 0.156 ND 112 0.0054 0.010 0.142 ND 1130.0025 0.0070  0.0195 ND 114 0.00693 0.0807 0.762 ND 115 0.00522 0.120.411 ND 116 0.00333 0.0984 0.183 ND 117 0.00609 0.00339 0.249 ND 1180.0992 0.367 ND ND 119 1.51 0.00669 1.51  ND 120 >0.238 0.158 ND ND 1210.0621 0.0072 ND ND 122 0.0391 0.00758 ND ND 123 0.0399 0.0056 ND ND 1240.0883 0.0101 ND ND 125 0.00847 0.189 0.606 ND 126 0.0545 0.276 ND ND127 0.0158 0.0938 0.128 ND 128 0.0478 0.182 ND ND 129 0.0159 0.087 0.249ND 130 0.0101 0.108 0.337 ND 131 0.0497 0.165 ND 0.827 132 0.0269 0.128ND 0.653 133 2.13 0.0203 ND ND 134 0.0234 0.00162 ND 0.238 135 0.05490.0231 ND ND 136 2.89 0.0822 ND >1 137 >4.77 0.0848 ND >1 138 0.08850.00738 ND 0.465 139 0.117 0.00716 ND 0.532 140 0.0938 0.00679 ND 0.491141 0.0868 0.0086 ND 0.443 142 0.0941 0.00576 ND 0.615 143 0.19 0.015 ND0.532 144 0.209 0.00234 ND 0.498 145 0.807 0.0087 ND ND 146 3.28 0.0501ND 9.32 147 0.761 0.0575 ND 6.32 148 5.72 0.00702 ND 1.68 149 0.002810.000669 ND 0.00118 150 2.68 0.0739 ND >10 151 0.813 0.00995 ND NV 1522.08 0.036 ND 8.14 153 1.04 0.00261 ND >10 154 1.04 0.0137 ND ND 1550.0237 0.364 ND ND 156 0.0268 0.0423 ND 0.332 157 0.387 0.0169 ND ND 1580.883 0.0285 ND ND 159 0.23 0.156 ND 0.599 160 1.71 0.00999 ND ND 1611.05 0.00316 ND 1.95 162 >12.7 0.0886 ND ND 163 0.00164 0.000605  0.0477ND ND = Not Determined

LPS (Lipopolysaccharide) Induced IL-6 Production Mouse Assay

Example 2 was assayed for its ability to inhibit LPS(lipopolysaccharide) induced IL-6 (Interleukin-6) production in mice.CD-1 female mice (Charles River Laboratories, 5 per group) received anintraperitoneal challenge of lipopolysaccharide (2.5 mg/kg, L2630 E.coli 0111:B4) one hour after oral administration of compound or compoundvehicle. Mice were euthanized 2 hours after lipopolysaccharideinjection, blood was removed by cardiac puncture, and then the serumharvested from the blood samples was frozen at −80° C. On the day of theassay the serum samples were brought to room temperature and thendiluted 1:20 in phosphate-buffered saline containing 2% bovine serumalbumin. Interleukin-6 measurements were performed using a cytokineassay from Meso Scale Discovery (Gaithersburg, Md.) for mouse serumanalysis according to the manufacturer's protocol and read on a SECTORImager 6000 (Meso Scale Discovery, Gaithersburg, Md.) instrument.Statistical analysis was performed using Prism software (version 5.0)incorporating Dunnett's one way ANOVA. The IL-6 mean and standarddeviation of the group of vehicle treated animals were compared with theIL-6 mean and standard deviation of the group treated with drug. A pvalue <0.05 means that there is less than a 5% probability that the meanvalues in the two groups are equal. Example 2 showed 45% inhibition witha p value of less than 0.05.

It is understood that the foregoing detailed description andaccompanying examples are merely illustrative and are not to be taken aslimitations upon the scope of the invention, which is defined solely bythe appended claims and their equivalents. Various changes andmodifications to the disclosed embodiments will be apparent to thoseskilled in the art. Such changes and modifications, including withoutlimitation those relating to the chemical structures, substituents,derivatives, intermediates, syntheses, formulations and/or methods ofuse of the invention, may be made without departing from the spirit andscope thereof. All publications, patents, and patent applications citedherein are hereby incorporated by reference in their entirety for allpurposes.

1. A compound of formula (I), or a pharmaceutically acceptable saltthereof:

wherein R^(x) is hydrogen or C₁-C₃ alkyl; R^(y) is hydrogen or C₁-C₃alkyl; A¹ is N or CR¹, A² is N or CR², A³ is N or CR³; and A⁴ is N orCR⁴; wherein zero, one, two, or three of A¹, A², A³, and A⁴ are N; R¹ ishydrogen, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, halogen, C₁-C₆haloalkyl, CN, or NO₂; R² is hydrogen, —S(O)₂R^(2a),—S(O)₂NR^(2b)R^(2c), —N(R^(2b))S(O)₂R^(2a), or —(C₁-C₆alkylenyl)-S(O)₂R^(2a); wherein R^(2a) is C₁-C₆ alkyl or C₁-C₆haloalkyl; and R^(2b) and R^(2c) are each independently hydrogen, C₁-C₆alkyl, or C₁-C₆ haloalkyl; L¹ is O, N(H), or OCH₂ wherein the CH₂ moietyof OCH₂ is attached to G¹; R^(x1), G¹, R³, and R⁴, are selected from(i), (ii), (iii), or (iv); (i) R^(x1) is —CN, -G^(x1)-G^(x2), —(C₁-C₆alkylenyl)-G^(x1)-G^(x2), —C(O)N(R^(xa))(R^(xb)), C₁-C₆ alkylsubstituted with one substituent selected from the group consisting of—CN, —OR^(xb), —SR^(xb), —S(O)R^(xb), —S(O)₂R^(xb), —NR^(xa)R^(xb),—C(O)R^(xb), —C(O)OR^(xb), —C(O)NR^(xa)R^(xb), and —S(O)₂NR^(xa)R^(xb);C₂-C₆ alkenyl, or C₂-C₆ alkynyl; wherein the C₂-C₆ alkenyl and C₂-C₆alkynyl are each independently substituted with one substituent selectedfrom the group consisting of —CN, —OR^(xc), —SR^(xc), —S(O)R^(xc),—S(O)₂R^(xc), —NR^(xa)R^(xc), —C(O)R^(xc), —C(O)OR^(xc),—C(O)NR^(xa)R^(xc), —S(O)₂NR^(xa)R^(xc), and G^(x1); G¹ is phenyl, C₃-C₆cycloalkyl, C₅-C₆ heteroaryl, or C₄-C₆ heterocycle; wherein each G¹ isindependently unsubstituted or substituted with 1, 2, 3, 4, or 5substituents independently selected from the group consisting of R^(u)and R^(v) groups; R³ is R^(1a), —C(O)OH, —C(O)NR^(3a)R^(3b),—NR^(3a)R^(3b), G^(3a), -G^(3a)-G^(3b), —(C₁-C₆ alkylenyl)-OR^(3a),—(C₁-C₆ alkylenyl)-NR^(3a)R^(3b), —(C₁-C₆ alkylenyl)-G^(3a), or —(C₁-C₆alkylenyl)-G^(3a)-G^(3b); and R⁴ is R^(1a) or G⁴; (ii) R^(x1) is —CN,-G^(x1)-G^(x2), —(C₁-C₆ alkylenyl)-G^(x1)-G^(x2),—C(O)N(R^(xa))(R^(xb)), hydrogen, C₂-C₆ alkenyl, C₂-C₆ alkynyl,—C(O)OR^(ax1), —C(O)NR^(bx1)R^(cx1), —C(O)R^(dx1), —S(O)₂R^(dx1),—S(O)₂NR^(bx1)R^(cx1), G^(x1), C₁-C₆ haloalkyl, or C₁-C₆ alkyl; whereinthe C₁-C₆ alkyl, C₂-C₆ alkenyl, and C₂-C₆ alkynyl are each optionallysubstituted with one substituent selected from the group consisting of—CN, —OR^(xc), —SR^(xc), —S(O)R^(xc), —S(O)₂R^(xc), —NR^(xa)R^(xc),—C(O)R^(xc), —C(O)OR^(xc), —C(O)NR^(xa)R^(xc), —S(O)₂NR^(xa)R^(xc), andG^(x1); G¹ is phenyl, C₃-C₆ cycloalkyl, C₅-C₆ heteroaryl, or C₄-C₆heterocycle; wherein each G¹ is substituted with one R^(u) group and isoptionally further substituted with 1, 2, 3, 4, or 5 R^(v) groups; R³ isR^(1a), —C(O)OH, —C(O)NR^(3a)R^(3b), —NR^(3a)R^(3b), G^(3a),-G^(3a)-G^(3b), —(C₁-C₆ alkylenyl)-OR^(3a), —(C₁-C₆alkylenyl)-NR^(3a)R^(3b), —(C₁-C₆ alkylenyl)-G^(3a), or —(C₁-C₆alkylenyl)-G^(3a)-G^(3b); and R⁴ is R^(1a) or G⁴; (iii) R^(x1) is —CN,-G^(x1)-G^(x2), —(C₁-C₆ alkylenyl)-G^(x1)-G^(x2),—C(O)N(R^(xa))(R^(xb)), hydrogen, C₂-C₆ alkenyl, C₂-C₆ alkynyl,—C(O)OR^(ax1), —C(O)NR^(bx1)R^(cx1), —C(O)R^(dx1), —S(O)₂R^(dx1),—S(O)₂NR^(bx1)R^(cx1), G^(x1), C₁-C₆ haloalkyl, or C₁-C₆ alkyl; whereinthe C₁-C₆ alkyl, C₂-C₆ alkenyl, and C₂-C₆ alkynyl are each optionallysubstituted with one substituent selected from the group consisting of—CN, —OR^(xc), —SR^(xc), —S(O)R^(xc), —S(O)₂R^(xc), —NR^(xa)R^(xc),—C(O)R^(xc), —C(O)OR^(xc), —C(O)NR^(xa)R^(xc), —S(O)₂NR^(xa)R^(xc), andG^(x1); G¹ is phenyl, C₃-C₆ cycloalkyl, C₅-C₆ heteroaryl, or C₄-C₆heterocycle; wherein each G¹ is independently unsubstituted orsubstituted with 1, 2, 3, 4, or 5 substituents independently selectedfrom the group consisting of R^(u) and R^(v) groups; R³ is —C(O)OH,—C(O)NR^(3a)R^(3b), —NR^(3a)R^(3b), G^(3a), -G^(3a)-G^(3b), —(C₁-C₆alkylenyl)-OR^(3a), —(C₁-C₆ alkylenyl)-NR^(3a)R^(3b), —(C₁-C₆alkylenyl)-G^(3a), or —(C₁-C₆ alkylenyl)-G^(3a)-G^(3b); and R⁴ is R^(1a)or G⁴; (iv) R^(x1) is —CN, -G^(x1)-G², —(C₁-C₆ alkylenyl)-G^(x1)-G^(x2),—C(O)N(R^(xa))(R^(xb)), hydrogen, C₂-C₆ alkenyl, C₂-C₆ alkynyl,—C(O)OR^(ax1), —C(O)NR^(bx1)R^(cx1), —C(O)R^(dx1), —S(O)₂R^(dx1),—S(O)₂NR^(bx1)R^(cx1), G^(x1), C₁-C₆ haloalkyl, or C₁-C₆ alkyl; whereinthe C₁-C₆ alkyl, C₂-C₆ alkenyl, and C₂-C₆ alkynyl are each optionallysubstituted with one substituent selected from the group consisting of—CN, —OR^(xc), —SR^(xc), —S(O)R^(xc), —S(O)₂R^(xc), —NR^(xa)R^(xc),—C(O)R^(xc), —C(O)OR^(xc), —C(O)NR^(xa)R^(xc), —S(O)₂NR^(xa)R^(xc), andG^(x1); G¹ is phenyl, C₃-C₆ cycloalkyl, C₅-C₆ heteroaryl, or C₄-C₆heterocycle; wherein each G¹ is independently unsubstituted orsubstituted with 1, 2, 3, 4, or 5 substituents independently selectedfrom the group consisting of R^(u) and R^(v) groups; R³ is R^(1a),—C(O)OH, —C(O)NR^(3a)R^(3b), —NR^(3a)R^(3b), G^(3a), -G^(3a)-G^(3b),—(C₁-C₆ alkylenyl)-OR^(3a), —(C₁-C₆ alkylenyl)-NR^(3a)R^(3b), —(C₁-C₆alkylenyl)-G^(3a), or —(C₁-C₆ alkylenyl)-G^(3a)-G^(3b); and R⁴ is G⁴;R^(xa), at each occurrence, is independently hydrogen, C₁-C₆ alkyl, orC₁-C₆ haloalkyl; R^(xb), at each occurrence, is independently C₁-C₆alkyl substituted with one substituent selected from the groupconsisting of —CN, —OR^(ax1), —SR^(ax1), —S(O)R^(dx1), —S(O)₂R^(dx1),—NR^(bx1)R^(cx1), —C(O)R^(ax1), —C(O)OR^(ax1), —C(O)NR^(bx1)R^(cx1), and—S(O)₂NR^(bx1)R^(cx1); R^(xc), at each occurrence, is independentlyhydrogen, C₁-C₆ alkyl, C₁-C₆ haloalkyl, G^(a), —(C₁-C₆ alkylenyl)-G^(a),or R^(xb); R^(ax1), R^(bx1), and R^(cx1), at each occurrence, are eachindependently hydrogen, C₁-C₆ alkyl, C₁-C₆ haloalkyl, G^(a), or —(C₁-C₆alkylenyl)-G^(a); R^(dx1), at each occurrence, is independently C₁-C₆alkyl, C₁-C₆ haloalkyl, G^(a), or —(C₁-C₆ alkylenyl)-G^(a); R^(1a), ateach occurrence, is independently hydrogen, C₁-C₆ alkyl, C₂-C₆ alkenyl,C₂-C₆ alkynyl, halogen, C₁-C₆ haloalkyl, CN, or NO₂; R^(3a) and R^(3b),at each occurrence, are each independently hydrogen, C₁-C₆ alkyl, C₁-C₆haloalkyl, G^(3a), -G^(3a)-G^(3b), —(C₁-C₆ alkylenyl)-G^(3a), —(C₁-C₆alkylenyl)-G^(3a)-G^(3b), or C₁-C₆ alkyl substituted with onesubstituents selected from the group consisting of —CN, —OR^(h),—SR^(h), —S(O)R^(i), —S(O)₂R^(h), —NR^(j)R^(k), —C(O)R^(h), —C(O)OR^(h),—C(O)NR^(j)R^(k), and —S(O)₂NR^(j)R^(k); G⁴, at each occurrence, isindependently phenyl, C₃-C₆ cycloalkyl, C₅-C₆ heteroaryl, or C₄-C₆heterocycle; each of which is optionally substituted with 1, 2, 3, 4, or5 substituents independently selected from the group consisting of C₁-C₆alkyl, NO₂, halogen, C₁-C₆ haloalkyl, —CN, oxo, —OR^(h), —SR^(h),—S(O)₂R^(h), and —NR^(j)R^(k); R^(u), at each occurrence, isindependently —(C₁-C₆ alkylenyl)-G^(u), —(C₂-C₆ alkynylene)-G^(u),—(C₁-C₆ alkylenyl)-SR^(h), —C(O)—Z¹, —C(O)—NZ¹Z², —S(O)₂—Z¹, —N(Z²)Z¹,or —N(Z²)S(O)₂—Z¹; wherein Z¹ is G^(u), —(C₁-C₆ alkylenyl)-G^(u),—(C₂-C₆ alkenylene)-G^(u), —(C₁-C₆ alkylenyl)-CN, —(C₁-C₆alkylenyl)-SR^(h), —(C₁-C₆ alkylenyl)-OR^(h), —(C₁-C₆alkylenyl)-NR^(j)R^(k), or —(C₁-C₆ alkylenyl)-C₁-C₄ alkoxy-C₁-C₄ alkoxy,and Z² is hydrogen, C₁-C₆ alkyl, or C₁-C₆ haloalkyl; G^(u), at eachoccurrence, is independently aryl, heteroaryl, heterocycle, cycloalkyl,or cycloalkenyl, wherein each G^(u) is independently unsubstituted orsubstituted with 1, 2, 3, 4, or 5 substituents independently selectedfrom the group consisting of C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl,halogen, C₁-C₆ haloalkyl, —CN, oxo, NO₂, —OR^(h), —O—(C₂-C₆alkylenyl)-NR^(j)R^(k), —OC(O)R^(i), —OC(O)NR^(j)R^(k), —O—(C₁-C₆alkylenyl)-NR^(j)R^(k), —SR^(h), —S(O)₂R^(h), —S(O)₂NR^(j)R^(k),—C(O)R^(h), —C(O)OR^(h), —C(O)NR^(j)R^(k), —NR^(j)R^(k), —N(R^(h))C(O)R,—N(R^(h))S(O)₂R^(i), —N(R^(h))C(O)O(R), —N(R^(h))C(O)NR^(j)R^(k),G^(ua), —(C₁-C₆ alkylenyl)-OR^(h), —(C₁-C₆ alkylenyl)-OC(O)R^(i),—(C₁-C₆ alkylenyl)-OC(O)NR^(j)R^(k), —(C₁-C₆ alkylenyl)-SR^(h), —(C₁-C₆alkylenyl)-S(O)₂R^(h), —(C₁-C₆ alkylenyl)-S(O)₂NR^(j)R^(k), —(C₁-C₆alkylenyl)-C(O)R^(h), —(C₁-C₆ alkylenyl)-C(O)OR^(h), —(C₁-C₆alkylenyl)-C(O)NR^(j)R^(k), —(C₁-C₆ alkylenyl)-NR^(j)R^(k), —(C₁-C₆alkylenyl)-N(R^(h))C(O)R^(i), —(C₁-C₆ alkylenyl)-N(R^(h))S(O)₂R^(i),—(C₁-C₆ alkylenyl)-N(R^(h))C(O)O(R^(i)), —(C₁-C₆alkylenyl)-N(R^(h))C(O)NR^(j)R^(k), —(C₁-C₆ alkylenyl)-CN, and —(C₁-C₆alkylenyl)-G^(a); G^(a), G^(x1), G^(x2), G^(3a), G^(3b), and G^(ua), ateach occurrence, are each independently aryl, heteroaryl, heterocycle,cycloalkyl, or cycloalkenyl, each of which is optionally substitutedwith 1, 2, 3, 4, or 5 R^(z) groups; R^(z) and R^(v), at each occurrence,are each independently C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl,halogen, C₁-C₆ haloalkyl, —CN, oxo, NO₂, —OR^(h), —OC(O)R^(i),—OC(O)NR^(j)R^(k), —SR^(h), —S(O)₂R^(h), —S(O)₂NR^(j)R^(k), —C(O)R^(h),—C(O)OR^(h), —C(O)NR^(j)R^(k), —NR^(j)R^(k), —N(R^(h))C(O)R,—N(R^(h))S(O)₂R^(i), —N(R^(h))C(O)O(R^(i)), —N(R^(h))C(O)NR^(j)R^(k),—(C₁-C₆ alkylenyl)-OR^(h), —(C₁-C₆ alkylenyl)-OC(O)R^(i), —(C₁-C₆alkylenyl)-OC(O)NR^(j)R^(k), —(C₁-C₆ alkylenyl)-SR^(h), —(C₁-C₆alkylenyl)-S(O)₂R^(h), —(C₁-C₆ alkylenyl)-S(O)₂NR^(j)R^(k), —(C₁-C₆alkylenyl)-C(O)R^(h), —(C₁-C₆ alkylenyl)-C(O)OR^(h), —(C₁-C₆alkylenyl)-C(O)NR^(j)R^(k), —(C₁-C₆ alkylenyl)-NR^(j)R^(k), —(C₁-C₆alkylenyl)-N(R^(h))C(O)R^(i), —(C₁-C₆ alkylenyl)-N(R^(h))S(O)₂R^(i),—(C₁-C₆ alkylenyl)-N(R^(h))C(O)O(R^(i)), —(C₁-C₆alkylenyl)-N(R^(h))C(O)NR^(j)R^(k), or —(C₁-C₆ alkylenyl)-CN; R^(h), R,R^(k), at each occurrence, are each independently hydrogen, C₁-C₆ alkyl,or C₁-C₆ haloalkyl; and R^(i), at each occurrence, is independentlyC₁-C₆ alkyl or C₁-C₆ haloalkyl.
 2. The compound of claim 1 or apharmaceutically acceptable salt thereof, wherein R^(x) is hydrogen, andR^(y) is C₁-C₃ alkyl.
 3. The compound of claim 2 or a pharmaceuticallyacceptable salt thereof, wherein A¹ is CR¹, A² is CR², A³ is CR³; and A⁴is CR⁴.
 4. The compound of claim 2 or a pharmaceutically acceptable saltthereof, wherein one of A¹, A², A³, and A⁴ is N.
 5. The compound ofclaim 2 or a pharmaceutically acceptable salt thereof, wherein R² ishydrogen, —S(O)₂R^(2a), or —N(R^(2b))S(O)₂R^(2a); R^(2a) is C₁-C₃ alkyl;and R^(2b) is hydrogen.
 6. The compound of claim 3 or a pharmaceuticallyacceptable salt thereof, wherein R^(y) is methyl, R¹ is hydrogen, andR^(x1), G¹, R³, and R⁴, are selected from (i).
 7. The compound of claim6 or a pharmaceutically acceptable salt thereof, wherein R³ is R^(1a);R⁴ is R^(1a); and G¹ is phenyl, C₃-C₆ cycloalkyl, or C₄-C₆ heterocycle,each of which is optionally substituted with 1, 2, 3, 4, or 5 R^(v)groups.
 8. The compound of claim 7 or a pharmaceutically acceptable saltthereof, wherein R^(1a) is hydrogen; and G¹ is phenyl or C₃-C₆cycloalkyl, each of which is optionally substituted with 1, 2, 3, 4, or5 R^(v) groups.
 9. The compound of claim 8 or a pharmaceuticallyacceptable salt thereof, wherein R^(x1) is -G^(x1)-G², —(C₁-C₆alkylenyl)-G^(x1)-G^(x2), —C(O)N(R^(xa))(R^(xb)), C₂-C₆ alkenyl, orC₂-C₆ alkynyl; wherein the C₂-C₆ alkenyl and C₂-C₆ alkynyl are eachindependently substituted with one substituent selected from the groupconsisting of —CN, —OR^(xc), —SR^(xc), —S(O)R^(xc), —S(O)₂R^(xc),—NR^(xa)R^(xc), —C(O)R^(xc), —C(O)OR^(xc), —C(O)NR^(xa)R^(xc),—S(O)₂NR^(xa)R^(xc), and G^(x1).
 10. The compound of claim 9 or apharmaceutically acceptable salt thereof, wherein R² is hydrogen,—S(O)₂R^(2a), or —N(R^(2b))S(O)₂R^(2a).
 11. The compound of claim 6 or apharmaceutically acceptable salt thereof, wherein the compound isselected from the group consisting of4-{2-[(2,2-difluorocyclopropyl)methoxy]-5-(ethylsulfonyl)phenyl}-6-methyl-2-{[4-(pyridin-4-yl)piperazin-1-yl]methyl}-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one;4-{2-[(2,2-difluorocyclopropyl)methoxy]-5-(ethylsulfonyl)phenyl}-6-methyl-2-{[4-(1,3-thiazol-2-yl)piperazin-1-yl]methyl}-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one;4-{2-[(2,2-difluorocyclopropyl)methoxy]-5-(ethylsulfonyl)phenyl}-6-methyl-2-{[4-(pyrazin-2-yl)piperazin-1-yl]methyl}-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one;4-{2-[(2,2-difluorocyclopropyl)methoxy]-5-(ethylsulfonyl)phenyl}-6-methyl-2-{[4-(pyrimidin-2-yl)piperazin-1-yl]methyl}-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one;4-{2-[(2,2-difluorocyclopropyl)methoxy]-5-(ethylsulfonyl)phenyl}-6-methyl-2-{[4-(pyridin-3-yl)piperazin-1-yl]methyl}-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one;4-{2-[(2,2-difluorocyclopropyl)methoxy]-5-(ethylsulfonyl)phenyl}-2-[3-(dimethylamino)prop-1-yn-1-yl]-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one;4-[2-(2,4-difluorophenoxy)-5-(methylsulfonyl)phenyl]-6-methyl-2-{[4-(1,3-thiazol-2-yl)piperazin-1-yl]methyl}-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one;2-[(4-cyclopropylpiperazin-1-yl)methyl]-4-[2-(2,4-difluorophenoxy)-5-(methylsulfonyl)phenyl]-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one;4-[2-(2,4-difluorophenoxy)-5-(methylsulfonyl)phenyl]-6-methyl-2-{[4-(tetrahydro-2H-pyran-4-yl)piperazin-1-yl]methyl}-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one;N-{4-(2,4-difluorophenoxy)-3-[2-(3-methoxyprop-1-yn-1-yl)-6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl]phenyl}ethanesulfonamide;4-[2-(2,4-difluorophenoxy)-5-(ethylsulfonyl)phenyl]-6-methyl-2-(1-phenyl-1H-pyrazol-5-yl)-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one;4-[2-(2,4-difluorophenoxy)-5-(ethylsulfonyl)phenyl]-6-methyl-2-[2-(morpholin-4-yl)pyridin-3-yl]-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one;4-[2-(2-chloro-6-methylphenoxy)-5-(ethylsulfonyl)phenyl]-N-(cyanomethyl)-6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-2-carboxamide;4-[2-(2-chloro-6-methylphenoxy)-5-(ethylsulfonyl)phenyl]-6-methyl-N-[1-(methylamino)-1-oxopropan-2-yl]-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-2-carboxamide;4-[2-(2-chloro-6-methylphenoxy)-5-(ethylsulfonyl)phenyl]-6-methyl-7-oxo-N-[2-oxo-2-(piperidin-1-yl)ethyl]-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-2-carboxamide;4-[2-(2-chloro-6-methylphenoxy)-5-(ethylsulfonyl)phenyl]-N-(2-cyanoethyl)-6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-2-carboxamide;4-[2-(2-chloro-6-methylphenoxy)-5-(ethylsulfonyl)phenyl]-6-methyl-N-[2-(methylamino)-2-oxoethyl]-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-2-carboxamide;4-[2-(2,4-difluorophenoxy)-5-(methylsulfonyl)phenyl]-6-methyl-2-{[4-(1-methylpiperidin-4-yl)piperazin-1-yl]methyl}-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one;4-[2-(2,4-difluorophenoxy)-5-(methylsulfonyl)phenyl]-6-methyl-2-{[4-(pyridin-2-yl)-1,4-diazepan-1-yl]methyl}-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one;4-[2-(2,4-difluorophenoxy)-5-(methylsulfonyl)phenyl]-2-{[3-(furan-2-yl)morpholin-4-yl]methyl}-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one;4-[2-(2,4-difluorophenoxy)-5-(methylsulfonyl)phenyl]-2-{[4-(3,5-dimethyl-4H-1,2,4-triazol-4-yl)piperidin-1-yl]methyl}-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one;4-[2-(2,4-difluorophenoxy)-5-(methylsulfonyl)phenyl]-2-{[3-(3,5-dimethyl-1H-pyrazol-1-yl)azetidin-1-yl]methyl}-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one;4-[2-(2,4-difluorophenoxy)-5-(methylsulfonyl)phenyl]-6-methyl-2-{[4-(morpholin-4-yl)piperidin-1-yl]methyl}-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one;4-[2-(2,4-difluorophenoxy)-5-(methylsulfonyl)phenyl]-6-methyl-2-{[2-(3-methyl-1,2,4-oxadiazol-5-yl)pyrrolidin-1-yl]methyl}-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one;4-[2-(2,4-difluorophenoxy)-5-(methylsulfonyl)phenyl]-6-methyl-2-{[4-(pyridin-2-yl)piperazin-1-yl]methyl}-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one;(2E)-3-{4-[2-(2,6-dimethylphenoxy)-5-(ethylsulfonyl)phenyl]-6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-2-yl}-N-ethylprop-2-enamide;2-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)-4-[2-(2,6-dimethylphenoxy)-5-(methylsulfonyl)phenyl]-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one;2-(3-cyclohexyl-1,2,4-oxadiazol-5-yl)-4-[2-(2,6-dimethylphenoxy)-5-(methylsulfonyl)phenyl]-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one;4-[2-(2,6-dimethylphenoxy)-5-(methylsulfonyl)phenyl]-6-methyl-2-(3-phenyl-1,2,4-oxadiazol-5-yl)-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one;4-[2-(2,6-dimethylphenoxy)-5-(methylsulfonyl)phenyl]-6-methyl-2-[3-(pyridin-3-yl)-1,2,4-oxadiazol-5-yl]-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one;4-[2-(2,6-dimethylphenoxy)-5-(methylsulfonyl)phenyl]-6-methyl-2-[3-(pyridin-2-yl)-1,2,4-oxadiazol-5-yl]-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one;4-[2-(2,6-dimethylphenoxy)-5-(methylsulfonyl)phenyl]-6-methyl-2-[3-(pyrazin-2-yl)-1,2,4-oxadiazol-5-yl]-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one;4-[2-(2,6-dimethylphenoxy)-5-(methylsulfonyl)phenyl]-6-methyl-2-[3-(tetrahydro-2H-pyran-4-yl)-1,2,4-oxadiazol-5-yl]-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one;4-[2-(2,6-dimethylphenoxy)-5-(methylsulfonyl)phenyl]-6-methyl-2-[3-(1,3-thiazol-4-yl)-1,2,4-oxadiazol-5-yl]-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one;N-[2-(diethylamino)-2-methylpropyl]-4-[2-(2,6-dimethylphenoxy)-5-(methylsulfonyl)phenyl]-6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-2-carboxamide;N-[4-(diethylamino)butyl]-4-[2-(2,6-dimethylphenoxy)-5-(methylsulfonyl)phenyl]-6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-2-carboxamide;4-[2-(cyclohexyloxy)-5-(ethylsulfonyl)phenyl]-6-methyl-2-[1-(piperidin-4-yl)-1H-pyrazol-4-yl]-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one;1-({4-[2-(2,4-difluorophenoxy)-5-(methylsulfonyl)phenyl]-6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-2-yl}methyl)-N,N-dimethyl-4-(2-oxopyrrolidin-1-yl)piperidine-4-carboxamide;4-[2-(2,4-difluorophenoxy)-5-(methylsulfonyl)phenyl]-6-methyl-2-{[3-(1H-1,2,4-triazol-1-yl)azetidin-1-yl]methyl}-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one;and3-[({4-[2-(2,4-difluorophenoxy)-5-(methylsulfonyl)phenyl]-6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-2-yl}methyl)amino]propanamide.12. The compound of claim 3 or a pharmaceutically acceptable saltthereof, wherein R^(y) is methyl, R¹ is hydrogen, and R^(x1), G¹, R³,and R⁴, are selected from (ii).
 13. The compound of claim 12 or apharmaceutically acceptable salt thereof, wherein R^(x1) is hydrogen or—C(O)NR^(bx1)R^(cx1); R³ is R^(1a); R⁴ is R^(1a); and G¹ is phenyl,C₃-C₆ cycloalkyl, or C₄-C₆ heterocycle, wherein each G¹ is substitutedwith one R^(u) group and is optionally further substituted with 1, 2, or3 R^(v) groups.
 14. The compound of claim 13 or a pharmaceuticallyacceptable salt thereof, wherein R^(1a) is hydrogen; and R² is hydrogen,—S(O)₂R^(2a), or —N(R^(2b))S(O)₂R^(2a).
 15. The compound of claim 12 ora pharmaceutically acceptable salt thereof, wherein the compound isselected from the group consisting ofN-cyclopropyl-3-[2-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-4-(methylsulfonyl)phenoxy]benzamide;6-methyl-4-[2-{3-[(4-methylpiperazin-1-yl)carbonyl]phenoxy}-5-(methylsulfonyl)phenyl]-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one;4-{2-[3-({4-[2-(1H-imidazol-1-yl)ethyl]piperazin-1-yl}carbonyl)phenoxy]-5-(methylsulfonyl)phenyl}-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one;6-methyl-4-[5-(methylsulfonyl)-2-(3-{[4-(pyrrolidin-1-yl)piperidin-1-yl]carbonyl}phenoxy)phenyl]-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one;N-cyclohexyl-3-[2-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-4-(methylsulfonyl)phenoxy]benzamide;4-[2-(3-{[4-(2-hydroxyethyl)piperazin-1-yl]carbonyl}phenoxy)-5-(methylsulfonyl)phenyl]-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one;3-[2-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-4-(methylsulfonyl)phenoxy]-N-[3-(2-oxopyrrolidin-1-yl)propyl]benzamide;4-[2-{3-[(4-cyclopentylpiperazin-1-yl)carbonyl]phenoxy}-5-(methylsulfonyl)phenyl]-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one;4-{2-[3-({4-[2-(dimethylamino)ethyl]piperazin-1-yl}carbonyl)phenoxy]-5-(methylsulfonyl)phenyl}-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one;4-[2-{3-[(4-acetylpiperazin-1-yl)carbonyl]phenoxy}-5-(methylsulfonyl)phenyl]-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one;6-methyl-4-[5-(methylsulfonyl)-2-(3-{[4-(trifluoromethyl)piperidin-1-yl]carbonyl}phenoxy)phenyl]-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one;N-(cyanomethyl)-N-methyl-3-[2-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-4-(methylsulfonyl)phenoxy]benzamide;N-[2-(dimethylamino)ethyl]-3-[2-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-4-(methylsulfonyl)phenoxy]benzamide;3-[2-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-4-(methylsulfonyl)phenoxy]-N-[(2R)-tetrahydrofuran-2-ylmethyl]benzamide;3-[2-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-4-(methylsulfonyl)phenoxy]-N-[2-(pyrrolidin-1-yl)ethyl]benzamide;N-(3,5-difluorobenzyl)-3-[2-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-4-(methylsulfonyl)phenoxy]benzamide;N-(2,4-difluorobenzyl)-3-[2-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-4-(methylsulfonyl)phenoxy]benzamide;N-{3-[2-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-4-(methylsulfonyl)phenoxy]phenyl}-1-phenylmethanesulfonamide;4-methoxy-N-{3-[2-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-4-(methylsulfonyl)phenoxy]phenyl}benzenesulfonamide;3-fluoro-N-{3-[2-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-4-(methylsulfonyl)phenoxy]phenyl}benzenesulfonamide;4-fluoro-N-{3-[2-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-4-(methylsulfonyl)phenoxy]phenyl}benzenesulfonamide;3-methoxy-N-{3-[2-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-4-(methylsulfonyl)phenoxy]phenyl}benzenesulfonamide;N-{3-[2-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-4-(methylsulfonyl)phenoxy]phenyl}-4-nitrobenzenesulfonamide;4-acetyl-N-{3-[2-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-4-(methylsulfonyl)phenoxy]phenyl}benzenesulfonamide;5-(dimethylamino)-N-{3-[2-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-4-(methylsulfonyl)phenoxy]phenyl}naphthalene-1-sulfonamide;N-{3-[2-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-4-(methylsulfonyl)phenoxy]phenyl}-4-(propan-2-yl)benzenesulfonamide;2,4-difluoro-N-{3-[2-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-4-(methylsulfonyl)phenoxy]phenyl}benzenesulfonamide;3-(difluoromethoxy)-N-{3-[2-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-4-(methylsulfonyl)phenoxy]phenyl}benzenesulfonamide;N-{3-[2-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-4-(methylsulfonyl)phenoxy]phenyl}cyclopropanesulfonamide;3-methyl-N-{3-[2-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-4-(methylsulfonyl)phenoxy]phenyl}benzenesulfonamide;N-{3-[2-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-4-(methylsulfonyl)phenoxy]phenyl}-3-nitrobenzenesulfonamide;4-fluoro-2-methyl-N-{3-[2-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-4-(methylsulfonyl)phenoxy]phenyl}benzenesulfonamide;3,4-dimethoxy-N-{3-[2-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-4-(methylsulfonyl)phenoxy]phenyl}benzenesulfonamide;N-{3-[2-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-4-(methylsulfonyl)phenoxy]phenyl}-4-(methylsulfonyl)benzenesulfonamide;2-cyano-N-{3-[2-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-4-(methylsulfonyl)phenoxy]phenyl}benzenesulfonamide;4-cyano-N-{3-[2-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-4-(methylsulfonyl)phenoxy]phenyl}benzenesulfonamide;3-cyano-N-{3-[2-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-4-(methylsulfonyl)phenoxy]phenyl}benzenesulfonamide;2-chloro-4-fluoro-N-{3-[2-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-4-(methylsulfonyl)phenoxy]phenyl}benzenesulfonamide;1-methyl-N-{3-[2-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-4-(methylsulfonyl)phenoxy]phenyl}-1H-imidazole-4-sulfonamide;3-[({3-[2-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-4-(methylsulfonyl)phenoxy]phenyl}amino)methyl]benzonitrile;4-[({3-[2-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-4-(methylsulfonyl)phenoxy]phenyl}amino)methyl]benzonitrile;4-[2-{3-[(4-fluorobenzyl)amino]phenoxy}-5-(methylsulfonyl)phenyl]-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one;4-[2-{3-[(2-methoxyethyl)amino]phenoxy}-5-(methylsulfonyl)phenyl]-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one;6-methyl-4-[5-(methylsulfonyl)-2-{3-[(tetrahydrofuran-2-ylmethyl)amino]phenoxy}phenyl]-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one;4-[2-{3-[(3-methoxybenzyl)amino]phenoxy}-5-(methylsulfonyl)phenyl]-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one;4-[2-{3-[(2-fluorobenzyl)amino]phenoxy}-5-(methylsulfonyl)phenyl]-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one;4-[2-{3-[(3-fluorobenzyl)amino]phenoxy}-5-(methylsulfonyl)phenyl]-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one;6-methyl-4-[5-(methylsulfonyl)-2-(3-{[3-(trifluoromethoxy)benzyl]amino}phenoxy)phenyl]-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one;4-[2-{3-[(2,4-dimethylbenzyl)amino]phenoxy}-5-(methylsulfonyl)phenyl]-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one;2-[({3-[2-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-4-(methylsulfonyl)phenoxy]phenyl}amino)methyl]benzonitrile;4-[2-{3-[(2-chloro-4-fluorobenzyl)amino]phenoxy}-5-(methylsulfonyl)phenyl]-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one;4-[2-{3-[(3,5-difluorobenzyl)amino]phenoxy}-5-(methylsulfonyl)phenyl]-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one;4-{2-[3-({4-[3-(dimethylamino)propoxy]benzyl}amino)phenoxy]-5-(methylsulfonyl)phenyl}-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one;4-[2-(3-{[3-(dimethylamino)benzyl]amino}phenoxy)-5-(methylsulfonyl)phenyl]-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one;4-[2-{3-[(2,3-dihydro-1,4-benzodioxin-6-ylmethyl)amino]phenoxy}-5-(methylsulfonyl)phenyl]-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one;6-methyl-4-[5-(methylsulfonyl)-2-{3-[(tetrahydrofuran-3-ylmethyl)amino]phenoxy}phenyl]-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one;N-{4-[({3-[2-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-4-(methylsulfonyl)phenoxy]phenyl}amino)methyl]phenyl}acetamide;4-[2-{3-[(4-methoxybenzyl)amino]phenoxy}-5-(methylsulfonyl)phenyl]-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one;4-[2-{3-[(cyclopropylmethyl)amino]phenoxy}-5-(methylsulfonyl)phenyl]-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one;4-[2-{3-[(2-cyclopentylethyl)amino]phenoxy}-5-(methylsulfonyl)phenyl]-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one;4-[2-{4-chloro-2-[3-(morpholin-4-yl)prop-1-yn-1-yl]phenoxy}-5-(ethylsulfonyl)phenyl]-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one;4-[2-{4-chloro-2-[3-(morpholin-4-yl)propyl]phenoxy}-5-(ethylsulfonyl)phenyl]-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one;6-methyl-4-[5-(methylsulfonyl)-2-{[1-(phenylsulfonyl)piperidin-4-yl]amino}phenyl]-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one;4-[2-({1-[(dimethylamino)acetyl]piperidin-4-yl}amino)-5-(methylsulfonyl)phenyl]-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one;6-methyl-4-[2-({1-[3-(methylsulfanyl)propyl]piperidin-4-yl}amino)-5-(methylsulfonyl)phenyl]-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one;N-{4-[(4-{[2-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-4-(methylsulfonyl)phenyl]amino}piperidin-1-yl)methyl]phenyl}acetamide;6-methyl-4-[5-(methylsulfonyl)-2-{[1-(3,4,5-trimethoxybenzyl)piperidin-4-yl]amino}phenyl]-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one;6-methyl-4-[5-(methylsulfonyl)-2-{[1-(thiophen-2-ylmethyl)piperidin-4-yl]amino}phenyl]-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one;4-{2-[(1-{4-[3-(dimethylamino)propoxy]benzyl}piperidin-4-yl)amino]-5-(methylsulfonyl)phenyl}-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one;6-methyl-4-[2-({1-[(methylsulfanyl)acetyl]piperidin-4-yl}amino)-5-(methylsulfonyl)phenyl]-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one;6-methyl-4-[5-(methylsulfonyl)-2-({1-[3-(2,3,4-trimethoxyphenyl)propanoyl]piperidin-4-yl}amino)phenyl]-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one;1-[(4-{[2-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-4-(methylsulfonyl)phenyl]amino}piperidin-1-yl)carbonyl]cyclopropanecarboxamide;4-[2-({1-[(4-methoxycyclohexyl)carbonyl]piperidin-4-yl}amino)-5-(methylsulfonyl)phenyl]-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one;4-[2-{[1-(methoxyacetyl)piperidin-4-yl]amino}-5-(methylsulfonyl)phenyl]-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one;6-methyl-4-[2-({1-[(4-methylpiperazin-1-yl)acetyl]piperidin-4-yl}amino)-5-(methylsulfonyl)phenyl]-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one;6-methyl-4-[5-(methylsulfonyl)-2-{[1-(pyrrolidin-1-ylacetyl)piperidin-4-yl]amino}phenyl]-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one;4-[2-({1-[(2-methoxyethoxy)acetyl]piperidin-4-yl}amino)-5-(methylsulfonyl)phenyl]-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one;6-methyl-4-[5-(methylsulfonyl)-2-({1-[3-(morpholin-4-yl)propanoyl]piperidin-4-yl}amino)phenyl]-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one;6-methyl-4-[2-({1-[(4-methylphenyl)acetyl]piperidin-4-yl}amino)-5-(methylsulfonyl)phenyl]-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one;4-[2-{[1-(benzylsulfonyl)piperidin-4-yl]amino}-5-(methylsulfonyl)phenyl]-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one;6-methyl-4-{5-(methylsulfonyl)-2-[(1-{[(E)-2-phenylethenyl]sulfonyl}piperidin-4-yl)amino]phenyl}-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one;N-{4-[(4-{[2-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-4-(methylsulfonyl)phenyl]amino}piperidin-1-yl)sulfonyl]phenyl}acetamide;4-[2-({1-[(4-methoxyphenyl)sulfonyl]piperidin-4-yl}amino)-5-(methylsulfonyl)phenyl]-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one;3-[(4-{[2-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-4-(methylsulfonyl)phenyl]amino}piperidin-1-yl)sulfonyl]benzonitrile;6-methyl-4-[5-(methylsulfonyl)-2-{[1-(thiophen-2-ylsulfonyl)piperidin-4-yl]amino}phenyl]-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one;6-methyl-4-[5-(methylsulfonyl)-2-({trans-4-[(thiophen-2-ylmethyl)amino]cyclohexyl}amino)phenyl]-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one;N-(4-{[(trans-4-{[2-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-4-(methylsulfonyl)phenyl]amino}cyclohexyl)amino]methyl}phenyl)acetamide;4-[2-({trans-4-[(2,4-difluorobenzyl)amino]cyclohexyl}amino)-5-(methylsulfonyl)phenyl]-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one;6-methyl-4-[5-(methylsulfonyl)-2-({trans-4-[(naphthalen-2-ylmethyl)amino]cyclohexyl}amino)phenyl]-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one;4-[2-({trans-4-[(2-methoxyethyl)amino]cyclohexyl}amino)-5-(methylsulfonyl)phenyl]-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one;6-methyl-4-{2-[(trans-4-{[3-(methylsulfanyl)propyl]amino}cyclohexyl)amino]-5-(methylsulfonyl)phenyl}-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one;4-[2-({trans-4-[(4-chlorobenzyl)amino]cyclohexyl}amino)-5-(methylsulfonyl)phenyl]-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one;4-[2-{2-[(cyclopropylmethyl)amino]-6-methylphenoxy}-5-(ethylsulfonyl)phenyl]-N-ethyl-6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-2-carboxamide;N-ethyl-4-[5-(ethylsulfonyl)-2-{2-methyl-6-[(tetrahydrofuran-3-ylmethyl)amino]phenoxy}phenyl]-6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-2-carboxamide;N-ethyl-4-{5-(ethylsulfonyl)-2-[2-methyl-6-(1H-pyrazol-1-ylmethyl)phenoxy]phenyl}-6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-2-carboxamide;N-ethyl-4-{5-(ethylsulfonyl)-2-[2-methyl-6-(morpholin-4-ylmethyl)phenoxy]phenyl}-6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-2-carboxamide;N-ethyl-4-{5-(ethylsulfonyl)-2-[2-methyl-6-(piperidin-1-ylmethyl)phenoxy]phenyl}-6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-2-carboxamide;N-ethyl-4-{5-(ethylsulfonyl)-2-[2-methyl-6-(2-phenylethyl)phenoxy]phenyl}-6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-2-carboxamide;N-ethyl-4-{5-(ethylsulfonyl)-2-[2-(1H-imidazol-1-ylmethyl)-6-methylphenoxy]phenyl}-6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-2-carboxamide;N-ethyl-4-[5-(ethylsulfonyl)-2-{2-methyl-6-[(2-oxopyrrolidin-1-yl)methyl]phenoxy}phenyl]-6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-2-carboxamide;4-[2-{2-[(1,1-dioxido-1,2-thiazolidin-2-yl)methyl]-6-methylphenoxy}-5-(ethylsulfonyl)phenyl]-N-ethyl-6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-2-carboxamide;N-ethyl-4-[5-(ethylsulfonyl)-2-{2-methyl-6-[(2-oxoazetidin-1-yl)methyl]phenoxy}phenyl]-6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-2-carboxamide;and N-ethyl-4-[5-(ethylsulfonyl)-2-{2-methyl-6-[(2-oxopyridin-1(2H)-yl)methyl]phenoxy}phenyl]-6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-2-carboxamide.16. The compound of claim 3 or a pharmaceutically acceptable saltthereof, wherein R^(y) is methyl, R¹ is hydrogen, and R^(x1), G¹, R³,and R⁴, are selected from (iii).
 17. The compound of claim 16 or apharmaceutically acceptable salt thereof, wherein R^(x1) is hydrogen or—C(O)NR^(bx1)R^(cx1); R⁴ is R^(1a); and G¹ is phenyl, C₃-C₆ cycloalkyl,or C₄-C₆ heterocycle, each of which is optionally substituted with 1, 2,3, 4, or 5 R^(v) groups.
 18. The compound of claim 17 or apharmaceutically acceptable salt thereof, wherein R^(1a) is hydrogen;and G¹ is phenyl or C₃-C₆ cycloalkyl, each of which is optionallysubstituted with 1, 2, 3, 4, or 5 R groups.
 19. The compound of claim 18or a pharmaceutically acceptable salt thereof, wherein R³ is —C(O)OH,—C(O)NR^(3a)R^(3b), G^(3a), —(C₁-C₆ alkylenyl)-OR^(3a), —(C₁-C₆alkylenyl)-NR^(3a)R^(3b), —(C₁-C₆ alkylenyl)-G^(3a), or —(C₁-C₆alkylenyl)-G^(3a)-G^(3b).
 20. The compound of claim 19 or apharmaceutically acceptable salt thereof, wherein R² is hydrogen,—S(O)₂R^(2a), or —N(R^(2b))S(O)₂R^(2a).
 21. The compound of claim 16 ora pharmaceutically acceptable salt thereof, wherein the compound isselected from the group consisting of4-[2-(cyclopropylmethoxy)-4-(3-methyl-H-pyrazol-5-yl)phenyl]-6-methyl-,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one;N-[4-(2,4-difluorophenoxy)-2-[(dimethylamino)methyl]-5-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)phenyl]ethanesulfonamide;N-[4-(2,4-difluorophenoxy)-5-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-2-(piperidin-1-ylmethyl)phenyl]ethanesulfonamide;N-[4-(2,4-difluorophenoxy)-5-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-2-(morpholin-4-ylmethyl)phenyl]ethanesulfonamide;N-{4-(2,4-difluorophenoxy)-5-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-2-[(4-methylpiperazin-1-yl)methyl]phenyl}ethanesulfonamide;N-[4-(2,4-difluorophenoxy)-2-(hydroxymethyl)-5-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)phenyl]ethanesulfonamide;N-{2-[(cyclopentylamino)methyl]-4-(2,4-difluorophenoxy)-5-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)phenyl}ethanesulfonamide;5-(2,4-difluorophenoxy)-2-[(ethylsulfonyl)amino]-4-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)benzamide;N-cyclopentyl-5-(2,4-difluorophenoxy)-2-[(ethylsulfonyl)amino]-4-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)benzamide;5-(2,4-difluorophenoxy)-2-[(ethylsulfonyl)amino]-N,N-dimethyl-4-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)benzamide;5-(2,4-difluorophenoxy)-2-[(ethylsulfonyl)amino]-4-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)benzoicacid;5-(2,4-difluorophenoxy)-2-[(ethylsulfonyl)amino]-4-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-N-(tetrahydro-2H-pyran-4-yl)benzamide;N-[4-(2,4-difluorophenoxy)-2-{[(2-hydroxyethyl)amino]methyl}-5-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)phenyl]ethanesulfonamide;N-{4-(2,4-difluorophenoxy)-5-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-2-[(2-phenylpyrrolidin-1-yl)methyl]phenyl}ethanesulfonamide;4-[2-(2,6-dimethylphenoxy)-4-{[2-(methylamino)-2-oxoethyl](pyridin-2-ylmethyl)carbamoyl}phenyl]-N-ethyl-6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-2-carboxamide;4-[2-(2,6-dimethylphenoxy)-4-{methyl[1-(propanoyloxy)piperidin-4-yl]carbamoyl}phenyl]-N-ethyl-6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-2-carboxamide;methyl3-[{3-(2,6-dimethylphenoxy)-4-[2-(ethylcarbamoyl)-6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl]benzoyl}(phenyl)amino]propanoate;4-[4-{benzyl[3-(morpholin-4-yl)propyl]carbamoyl}-2-(2,6-dimethylphenoxy)phenyl]-N-ethyl-6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-2-carboxamide;and4-[4-{(3,4-dichlorophenyl)[2-(thiomorpholin-4-yl)ethyl]carbamoyl}-2-(2,6-dimethylphenoxy)phenyl]-N-ethyl-6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-2-carboxamide.22. The compound of claim 3 or a pharmaceutically acceptable saltthereof, wherein R^(y) is methyl, R¹ is hydrogen, and R^(x1), G¹, R³,and R⁴, are selected from (iv).
 23. The compound of claim 22 or apharmaceutically acceptable salt thereof, wherein R^(x1) is hydrogen; R³is R^(1a); and G¹ is phenyl, C₃-C₆ cycloalkyl, or C₄-C₆ heterocycle,each of which is optionally substituted with 1, 2, 3, 4, or 5 R^(v)groups.
 24. The compound of claim 23 or a pharmaceutically acceptablesalt thereof, wherein R^(1a) is hydrogen; and G¹ is phenyl or C₃-C₆cycloalkyl, each of which is optionally substituted with 1, 2, 3, 4, or5 R^(v) groups.
 25. The compound of claim 24 or a pharmaceuticallyacceptable salt thereof, wherein R⁴ is optionally substituted C₃-C₆cycloalkyl.
 26. The compound of claim 25 or a pharmaceuticallyacceptable salt thereof, wherein R⁴ is optionally substitutedcyclopropyl, and R² is hydrogen, —S(O)₂R^(2a), or —N(R^(2b))S(O)₂R^(2a).27. The compound of claim 22 or a pharmaceutically acceptable saltthereof, wherein the compound isN-[3-cyclopropyl-4-(2,4-difluorophenoxy)-5-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)phenyl]ethanesulfonamide.28. A pharmaceutical composition comprising a therapeutically effectiveamount of a compound of formula (I) according to claim 1, or apharmaceutically acceptable salt thereof, in combination with apharmaceutically acceptable carrier.
 29. A method for treating cancer ina subject comprising administering a therapeutically effective amount ofa compound of formula (I) according to claim 1 or a pharmaceuticallyacceptable salt thereof, to a subject in need thereof.
 30. The method ofclaim 29 wherein the cancer is selected from the group consisting of:acoustic neuroma, acute leukemia, acute lymphocytic leukemia, acutemyelocytic leukemia (monocytic, myeloblastic, adenocarcinoma,angiosarcoma, astrocytoma, myelomonocytic and promyelocytic), acutet-cell leukemia, basal cell carcinoma, bile duct carcinoma, bladdercancer, brain cancer, breast cancer, bronchogenic carcinoma, cervicalcancer, chondrosarcoma, chordoma, choriocarcinoma, chronic leukemia,chronic lymphocytic leukemia, chronic myelocytic (granulocytic)leukemia, chronic myelogenous leukemia, colon cancer, colorectal cancer,craniopharyngioma, cystadenocarcinoma, diffuse large B-cell lymphoma,dysproliferative changes (dysplasias and metaplasias), embryonalcarcinoma, endometrial cancer, endotheliosarcoma, ependymoma, epithelialcarcinoma, erythroleukemia, esophageal cancer, estrogen-receptorpositive breast cancer, essential thrombocythemia, Ewing's tumor,fibrosarcoma, follicular lymphoma, germ cell testicular cancer, glioma,glioblastoma, gliosarcoma, heavy chain disease, hemangioblastoma,hepatoma, hepatocellular cancer, hormone insensitive prostate cancer,leiomyosarcoma, leukemia, liposarcoma, lung cancer,lymphagioendotheliosarcoma, lymphangiosarcoma, lymphoblastic leukemia,lymphoma (Hodgkin's and non-Hodgkin's), malignancies andhyperproliferative disorders of the bladder, breast, colon, lung,ovaries, pancreas, prostate, skin and uterus, lymphoid malignancies ofT-cell or B-cell origin, leukemia, lymphoma, medullary carcinoma,medulloblastoma, melanoma, meningioma, mesothelioma, multiple myeloma,myelogenous leukemia, myeloma, myxosarcoma, neuroblastoma, NUT midlinecarcinoma (NMC), non-small cell lung cancer, oligodendroglioma, oralcancer, osteogenic sarcoma, ovarian cancer, pancreatic cancer, papillaryadenocarcinomas, papillary carcinoma, pinealoma, polycythemia vera,prostate cancer, rectal cancer, renal cell carcinoma, retinoblastoma,rhabdomyosarcoma, sarcoma, sebaceous gland carcinoma, seminoma, skincancer, small cell lung carcinoma, solid tumors (carcinomas andsarcomas), small cell lung cancer, stomach cancer, squamous cellcarcinoma, synovioma, sweat gland carcinoma, thyroid cancer,Waldenstrom's macroglobulinemia, testicular tumors, uterine cancer andWilms' tumor.
 31. A method for treating a disease or condition in asubject comprising administering a therapeutically effective amount of acompound of formula (I) according to claim 1 or a pharmaceuticallyacceptable salt thereof, to a subject in need thereof, wherein saiddisease or condition is selected from the group consisting of Addison'sdisease, acute gout, ankylosing spondylitis, asthma, atherosclerosis,Behcet's disease, bullous skin diseases, cardiac myopathy, cardiachypertrophy, chronic obstructive pulmonary disease (COPD), Crohn'sdisease, dermatitis, eczema, giant cell arteritis, glomerulonephritis,heart failure, hepatitis, hypophysitis, inflammatory bowel disease,),Kawasaki disease, lupus nephritis, multiple sclerosis, myocarditis,myositis, nephritis, organ transplant rejection, osteoarthritis,pancreatitis, pericarditis, Polyarteritis nodosa, pneumonitis, primarybiliary cirrhosis, psoriasis, psoriatic arthritis, rheumatoid arthritis,scleritis, sclerosing cholangitis, sepsis systemic lupus erythematosus,Takayasu's Arteritis, toxic shock, thyroiditis, type I diabetes,ulcerative colitis, uveitis, vitiligo, vasculitis, and Wegener'sgranulomatosis.
 32. A method for treating a disease or condition in asubject comprising administering a therapeutically effective amount of acompound of formula (I) according to claim 1 or a pharmaceuticallyacceptable salt thereof, to a subject in need thereof, wherein saiddisease or condition is selected from the group consisting of: diabeticnephropathy, hypertensive nephropathy, HIV-associated nephropathy,glomerulonephritis, lupus nephritis, IgA nephropathy, focal segmentalglomerulosclerosis, membranous glomerulonephritis, minimal changedisease, polycystic kidney disease and tubular interstitial nephritis.33. A method for treating an acquired immunodeficiency syndrome (AIDS)in a subject comprising administering a therapeutically effective amountof a compound of formula (I) according to claim 1 or a pharmaceuticallyacceptable salt thereof, to a subject in need thereof.
 34. A method fortreating a disease or condition in a subject comprising administering atherapeutically effective amount of a compound of formula (I) accordingto claim 1 or a pharmaceutically acceptable salt thereof, to a subjectin need thereof, wherein said disease or condition is selected from thegroup consisting of: obesity, dyslipidemia, hypercholesterolemia,Alzheimer's disease, metabolic syndrome, hepatic steatosis, type IIdiabetes, insulin resistance, diabetic retinopathy and diabeticneuropathy.
 35. A method of contraception in a male subject comprisingadministering a therapeutically effective amount of a compound offormula (I) according to claim 1 or a pharmaceutically acceptable saltthereof, to a subject in need thereof.
 36. A method for treating anacute kidney disease or condition in a subject comprising administeringa therapeutically effective amount of a compound of formula (I)according to claim 1 or a pharmaceutically acceptable salt thereof, to asubject in need thereof, wherein said acute kidney disease or conditionis selected from the group consisting of: ischemia-reperfusion inducedkidney disease, cardiac and major surgery induced kidney disease,percutaneous coronary intervention induced kidney disease,radio-contrast agent induced kidney disease, sepsis induced kidneydisease, pneumonia induced kidney disease, and drug toxicity inducedkidney disease.
 37. The method of claim 36, further comprisingadministering a therapeutically effective amount of at least oneadditional therapeutic agent.
 38. A method of treating a chronic kidneydisease or condition in a subject comprising administering atherapeutically effective amount of a compound of formula (I) accordingto claim 1 or a pharmaceutically acceptable salt thereof, to a subjectin need thereof, wherein said disease or condition is selected from thegroup consisting of: diabetic nephropathy, hypertensive nephropathy,HIV-associated nephropathy, glomerulonephritis, lupus nephritis, IgAnephropathy, focal segmental glomerulosclerosis, membranousglomerulonephritis, minimal change disease, polycystic kidney diseaseand tubular interstitial nephritis.
 39. The method of claim 38, furthercomprising administering a therapeutically effective amount of at leastone additional therapeutic agent.